www.rsc.org/pps | Photochemical & Photobiological Sciences
PERSPECTIVE
Recent advances in urocanic acid photochemistry, photobiology and
photoimmunology
Neil K. Gibbs,*a Joanne Tyea and Mary Norvalb
Received 12th November 2007, Accepted 22nd February 2008
First published as an Advance Article on the web 13th March 2008
DOI: 10.1039/b717398a
Urocanic acid (UCA), produced in the upper layers of mammalian skin, is a major absorber of
ultraviolet radiation (UVR). Originally thought to be a ‘natural sunscreen’, studies conducted a quarter
of a century ago proposed that UCA may be a chromophore for the immunosuppression that follows
exposure to UVR. With its intriguing photochemistry, its role in immunosuppression and skin cancer
development, and skin barrier function, UCA continues to be the subject of intense research effort.
This review summarises the photochemical, photobiological and photoimmunological findings
regarding UCA, published since 1998.
Introduction
Urocanic acid (UCA) is formed in the upper layers of the epidermis
where filaggrin, a histidine-rich filamentous protein produced after
caspase-14 cleavage of profilaggrin, is broken down by proteinases
into component amino acids.1 It is synthesised as the trans-isomer
(trans-UCA) from histidine in a deamination reaction, catalysed
by histidase (histidine ammonia-lyase). Trans-UCA accumulates
in the skin to high concentration (at least 6 nmol cm−2 of surface
skin in most human subjects) as the enzyme urocanase, that
catalyses trans-UCA catabolism, is not present in this site. In
the inherited metabolic condition, histidinaemia, mutations in the
histidase gene result in an accumulation of histidine and lower
or non-existent levels of UCA.2 UCA is the principal protondonating species in the stratum corneum and is therefore crucial
a
Dermatological Sciences, University of Manchester Medical School,
Stopford Building, Oxford Road, Manchester, UK M13 9PT.
E-mail: [email protected]; Tel: (44) 161-275-5505; Fax: (44)
161-275-5289
b
Biomedical Sciences, University of Edinburgh Medical School, Edinburgh,
Scotland
to efficient epidermal barrier function.3,4 It is released as terminally
differentiated corneocytes slough off and is also eluted from the
stratum corneum by sweat.
Trans (E)-UCA is a major chromophore in the epidermis. On
absorption of ultraviolet radiation (UVR), it converts to the cis
(Z)-isomer (see Fig. 1). This reaction is dose-dependent until a
photostationary state is reached when the concentration of cisUCA is approximately 60–70%. The action spectrum for trans to
cis isomerisation shows a peak at 300–315 nm in mouse skin5,6
and at 280–310 nm in human skin.7 Photoisomerisation still
takes place as a result of UVA-II (320–340 nm) or UVA-I (340–
400 nm) radiation.6–8 It has been noted that certain epidermal
microflora can degrade L-histidine, trans-UCA and cis-UCA, and
one bacterial species that catabolises cis-UCA has been identified
as Micrococcus luteus.9
Trans-UCA absorbs erythemogenic UVB (290–315 nm) radiation and was initially proposed to play a role in natural photoprotection, leading to its incorporation in commercial sunscreens
and cosmetics from the 1960s until its use was discontinued in
the 1990s. More recent evidence demonstrated that trans-UCA
is an ineffective sunscreen.10 In 1983, De Fabo and Noonan
Neil Gibbs, PhD, is a Lecturer in Dermatological Sciences, The
University of Manchester, UK, with major research interests in human
skin photobiology.
Joanne Tye, MSc, is a British Skin Foundation funded PhD student in
Dermatological Sciences, The University of Manchester, UK, studying
immunological aspects of human skin photobiology.
Mary Norval, DSc, is Professor Emeritus at the University of Edinburgh
in Scotland, with major research interests in the effects of ultraviolet
radiation on human health, especially immunological aspects.
Neil K. Gibbs
Mary Norval
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Photochem. Photobiol. Sci., 2008, 7, 655–667 | 655
Fig. 1 The photoisomerisation of naturally occurring trans (E)-urocanic
acid to cis (Z)-urocanic acid.
suggested that UCA could act as an initiator in the complex
pathway leading to UVR-induced immunosuppression.11 Since
that date many experiments in vivo and in vitro have confirmed
this role, although, as described in detail below, several intriguing
uncertainties remain, especially regarding its mode of action in
modulating immune responses.
The present review follows from ones published in 199512
and 1999,13 and focuses on recent advances, concentrating on
information available since 1998. First there is a section on
UCA photochemistry relevant to its photobiological properties,
followed by another in which results from the analysis of UCA isomers are brought together. The following section evaluates several
proposed mechanisms whereby cis-UCA could downregulate cellmediated immunity. The role of cis-UCA in the immunological
control of infectious diseases and photocarcinogenesis are then
considered, before a final section summarises strategies to protect
against the immunosuppressive effects of cis-UCA.
Photochemistry of UCA
On absorbing UVR, trans-UCA isomerises to cis-UCA with an
efficiency that is dependent on solvent polarity.14 It has been
known for over twenty years that, in an aqueous solution, the
quantum yield (U) for this reaction is wavelength dependent with
peak photoisomerisation efficiency (U = 0.49) at 310 nm but
almost an order of magnitude lower efficiency (U = 0.05) at the
trans-UCA absorption maximum of 268 nm.15 The mechanism for
this wavelength dependency has been elucidated by Hanson and
Simon16 who used pulsed-laser acoustic spectroscopy with excitation at 264 nm and 310 nm. With 264 nm excitation, trans-UCA
forms a singlet state and very efficiently undergoes intersystem
crossing to a long lived triplet state. In contrast, after 310 nm
excitation, singlet trans-UCA intersystem crossing is marginal
and the singlet state predominantly undergoes photoisomerisation
to cis-UCA. Further studies using two-pulse laser excitation
demonstrated that trans-UCA exists as different electronic states
that all contribute to the overall absorption spectrum of transUCA but have unique photoreactivity.16 These different states were
explored by Ryan and Levy17 who used dispersed emission studies
of a supersonic jet of gaseous-phase trans-UCA and identified
three distinct regions in its steady-state fluorescence excitation
spectrum corresponding to (I) formation of the lowest trans-UCA
singlet state, S1 , (II) formation of the S1 states of both trans-UCA
and cis-UCA isomers indicating that photoisomerisation occurs
efficiently and (III) formation of the S2 trans-UCA excited state
which does not result in isomerisation. A consequence of these
competing photoprocesses, the wavelength dependent U for UCA
photoisomerisation and high absorption of superficial stratum
corneum proteins5 is that the action spectra for the production
of cis-UCA in mouse and human skin in vivo are red-shifted from
656 | Photochem. Photobiol. Sci., 2008, 7, 655–667
the trans-UCA absorption spectrum (maximal at 268 nm) and
have broad peaks of 280–310 nm.6,7
The trans-UCA triplet state has a triplet energy (E T ) of about
230 kJ mol−1 and a lifetime of approximately 10−7 s−1 and is
capable of energy transfer to molecular (triplet state) oxygen to
form singlet oxygen, O2 (1 Dg ).13,16,18–21 Photoacoustic spectroscopy
has determined that this weak reaction occurs in the UVA region
of 315–380 nm with peak efficiency at 340 nm16 which corresponds
with a theoretical efficiency spectrum for trans-UCA intersystem
crossing.18 Time-dependent density functional theory calculations
support the existence of this transition at 340 nm.22,23 The shape
of the action spectrum for trans-UCA photosensitized production
of O2 (1 Dg ) mimics that for the production of sagging in mouse
skin.24 It has therefore been suggested that trans-UCA may be
a chromophore for O2 (1 Dg ) mediated skin aging.16,22 As O2
(1 Dg ) is short-lived and only reacts with adjacent molecules, it
remains to be determined whether UCA photosensitized O2 (1 Dg )
formation in the terminally differentiated stratum corneum can
influence cytokine and matrix metalloproteinase induction lower
in the epidermis. There is evidence that trans-UCA photosensitized
O2 (1 Dg ) generated during UVA irradiation can be scavenged
inefficiently (kQ = 3.5 × 106 M−1 s−1 ) by ground state transUCA and form coloured oxidized UCA products that are more
efficient than parent UCA at photosensitising O2 (1 Dg ) production
and hence further UCA decomposition.18 These UCA oxidized
products include longer lived hydroperoxides that are capable of
cleaving plasmid DNA19 and inactivating viruses.20 In contrast to
these type II reactions, UCA has been reported to act as a type I
photosensitiser when exposed to UVA (355 nm) in the presence of
methyl linoleate.25 When irradiated at 266 nm, both trans- and cisUCA also undergo photo-ionisation to form a long-lived radical
that can efficiently react with oxygen (kQ = 1.3 × 109 M−1 s−1 ).26
In addition to its ability to photosensitise production of excited
oxygen species, trans-UCA is an effective hydroxyl scavenger,
although an inefficient peroxyl radical scavenger.27,28 In vitro
studies using hydroxyl radical generating systems suggest that
several UCA oxidation products may be produced from both transUCA and cis-UCA after UVB exposure, particularly imidazole4-carboxaldehyde (ImCHO), its oxidation product imidazole4-carboxylic acid (ImCOOH), imidazole-4-acetic acid (ImAc)
and glyoxylic acid (GLX). Under more physiological conditions,
ImCHO, ImAc and ImCOOH were shown to be formed in corneal
scrapings of human skin after UVB, but not UVA irradiation.29
It is notable that certain of these UCA photoxidation products
also possess immunosuppressive properties comparable to those
of cis-UCA.30
Analysis of UCA isomers
Methods
There are various methods which can be used to measure UCA
in biological tissues. The most common utilises high performance
liquid chromatography (HPLC). A wide variety of columns and
eluting buffers have been reported for the quantification of
UCA isomers. The amount of free histidine is a major factor
affecting the level of UCA in the skin. It is therefore useful to
analyse skin histidine and UCA levels simultaneously. Tateda and
colleagues31 have developed a HPLC method which detects UCA
This journal is © The Royal Society of Chemistry and Owner Societies 2008
through UVR absorption, and histidine by fluorescence following
postcolumn derivatisation with o-phthalaldehyde. Hermann and
Abeck32 also reported optimal separation of UCA isomers and
histidine using a C8 column and a mobile phase consisting of
90% aqueous (0.01 M triethylammoniumphosphate with 5 mM
sodium 1-octanesulfonate) and 10% acetonitrile. The same group
also describe another technique which can detect UCA isomers
and histidine using high-performance capillary electrophoresis
(HPCE). UCA isomers are separated from histidine on a fusedsilica column with a mobile phase of 0.05M NaH2 PO4 buffer at
a pH of 5.0.32 Levels of UCA are similar to those obtained by
HPLC. In contrast to these extraction/chromatographic methods
Caspers and co-workers33 have developed a confocal Raman
microspectroscopy system that enables the levels of total UCA
in skin to be measured non-invasively, although this apparatus
cannot distinguish between the two UCA isomers.
Concentration of urocanic acid in skin
UCA is synthesised from histidine in a deamination reaction. Total
UCA concentration appears to correlate with increasing dietary
L-histidine levels so that, for instance, skin UCA content has been
shown to rise in rats or mice fed diets rich in histidine.34,35 A study
in mice examined the relationship between dietary histidine levels
and UCA isomers in the skin after a single exposure to UVR at
312 nm.36 The group fed the histidine-rich diet had the same ratio
of cis:trans-UCA after irradiation as the group fed the normal diet
but showed a quicker return to baseline UCA isomer levels.
Further interest in dietary constituents and UCA has focussed
on malnutrition. For example De Fabo et al.35 found that low levels
of dietary L-histidine resulted in an increase in skin trans-UCA in
mice, consistent with the weight loss observed. This change might
lead to increased immunosuppression following sunlight exposure
because of the increased production of cis-UCA. Hug et al.37 have
suggested that such a reduction in the immune response could
be a factor contributing to the increased incidence of infectious
diseases in malnourished children in many developing countries.
In an interesting extension of this idea, Hug et al.38 speculate that
the high levels of infection seen in astronauts, who are also known
to suffer protein loss, may be related to enhanced UCA levels with
UVR, either from the sun or spacecraft lighting, leading to the
production of immunosuppressive cis-UCA. In a similar manner,
travellers to high altitude can become malnourished, suffer protein
catabolism, are exposed to enhanced solar UVB and often develop
infectious diseases.39 These novel ideas have not yet been tested
experimentally.
The concentration of UCA in the skin of healthy individuals of
different phototypes and at different body sites has been measured.
It varied considerably between individuals at all body sites, with
more than 10-fold differences being found.40,41 No correlation
between UCA content and age, sex, minimal erythema dose
(MED), phototype, pigment or stratum corneum thickness was
apparent; any biological consequence of these large individual
differences in UCA concentration remains unknown,41 although
it has been suggested in a preliminary study that people with high
UCA levels produce more DNA photoproducts, with a slower
rate of repair of such lesions.42 Within each subject, there are only
slight variation in UCA concentration between one body site and
another, with higher levels being present in the buttock and arm
and lower levels in the forehead. A further study examined UCA
isomers in the skin of healthy children.43 As is the case in adults,
there was no correlation between total UCA concentration and
MED. However the UCA content was significantly higher in the
children than in adults at an unexposed site (buttock–median 22.2
vs. 13.6 nmol cm−2 ), but not different on a sun-exposed site (upper
back), although a significantly higher percentage as cis-UCA was
found in children compared with adults at this site (median 60.1
vs. 28.3%). This may reflect a higher degree of sun exposure in
children than in adults in the weeks or days preceding the analysis.
Alternatively, but less likely, is the possibility that children suffer
a greater degree of immunosuppression following UVR exposure.
In adults, the UCA content at both exposed and unexposed body
sites decreased slightly in the summer months compared with
the rest of the year (for example mean 7.2 nmol cm−2 in August
vs. 9.0 nmol cm−2 in December on the forehead).44 This may be
due to more extensive sweating and hence loss of UCA in the
hotter temperatures of the summer, and argues against a role
for UCA in natural photoprotection. Indeed it has been shown
that UCA concentration in human skin does not correlate with
photosensitivity.10
There are differences in UCA levels between species. While
a median value of approximately 20 nmol cm−2 is present in
human skin, the marsupial opossum, Monodelphis domestica, has
about 12 nmol cm−2 and a range of Australian marsupials about
120 nmol cm−2 , most of which appeared to be present in the dermis,
rather than in the epidermis, as is the case for human and mouse
skin.45 One study of hairless mice reported a value of 5 nmol cm−2 .36
The skin concentration of UCA is known to vary considerably
between strains of haired mice (A. Moodycliffe and M. Norval,
unpublished).
Photoisomerisation of urocanic acid
Exposure to UVR induces a dose-dependent isomerisation from
trans to cis-UCA, ultimately resulting in approximately 60-70%
cis-UCA at the photostationary point, following four standard
erythema doses of broadband UVB of human subjects.46 This
amount of UVR would be expected to produce moderate erythema
on unclimatised white skin but minimal or no erythema on
previously exposed skin.47 The analysis of a group of subjects
throughout a year revealed that, in the summer, cis-UCA levels are
close to the maximum obtainable at all body sites tested (forehead,
upper back, upper chest and outer and inner upper arm) except
at a non-exposed site (buttock).41 In the winter months the UCA
present as the cis-isomer fell to below 7% in all regions apart from
the forehead where it remained at 18%.
The relationship between the degree of pigmentation and the
production of cis-UCA following UVR has been examined.
Snellman et al. found no skin phototype-dependent difference
in the ability to photoisomerise UCA.48 It should be noted that,
in this study, the irradiations were performed with fractions of
the MED calculated for each subject on an individual basis,
implying that the darker-skinned individuals would receive higher
UV doses that the fairer-skinned individuals. In contrast, de
Fine Olivarius et al. demonstrated that the production of cisUCA was higher in subjects of skin types I and II compared
with skin types III and IV following exposure to small doses
of UVR.46 Thus, as the immunological activity of cis-UCA is
This journal is © The Royal Society of Chemistry and Owner Societies 2008
Photochem. Photobiol. Sci., 2008, 7, 655–667 | 657
dose-dependent, at least in mice,34,49 low pigmentation may be
considered as a risk factor for a higher degree of UV-induced
immunosuppression. The increase in cis-UCA following UVR
suggests that it may be possible to assess recent sun exposure
by analysing the ratio of cis:trans-UCA in human urine. Sastry
et al. tested this by measuring the concentration of UCA isomers
in such samples before and following irradiation with 95%
UVA/5% UVB to 90% of the body area, a protocol similar to
that experienced in commercial suntanning parlours.50 A single
exposure or repeated daily exposures of approximately 70% MED
induced about a 5-fold increase in the ratio relative to baseline.
Thus such an assay may be useful as a biomarker for recent sun
exposure.
Although photoisomerisation of UCA in human skin occurs
optimally within the UVB region,6 both UVA-II and UVA-I have
also been shown to induce cis-UCA production.6,8 Commercial
sun beds emit mainly UVA wavelengths. Possible consequences of
sunbed use on cis-UCA formation, immunosuppression and the
induction of skin cancer remain unclear. Ruegemer et al.51 assessed
UCA levels in volunteers before sunbed use and after twice weekly
exposures for 6 weeks. They report an initial decrease in transUCA which then rose after the 12 sessions, and a significant
increase in cis-UCA at most of the time points measured. These
data suggest that consecutive sunbed use alters the total content
and isomer ratio of UCA, indicating that a continuing detrimental
effect on the immune system is possible during the development
of a tan.
As cis-UCA could be an important factor in cutaneous carcinogenesis (see ‘Role of cis-UCA in photocarcinogenesis’ section
below), UCA isomer biomarkers may be useful in predicting the
risk of developing skin cancer. This possibility has been tested by
three groups. First de Fine Olivarius et al. assayed UCA isomers
in UV-exposed and non-exposed body sites in patients with a past
history of basal cell carcinoma (BCC) or cutaneous malignant
melanoma (CMM) and in healthy controls.52 No differences were
found between the groups in total UCA or in the percentage as
the cis-isomer. The net production of cis-UCA (measured as a
percentage of trans-UCA) following a single test UV dose was
slightly higher in both cancer groups compared with the control
group. However the biological significance of this change was
thought doubtful as there was no difference between the groups in
the absolute concentration of cis-UCA (measured as nmol cm−2 )
induced by the UVR. Similar results were recorded by Snellman
et al. after analysis of patients with past histories of BCC or
CMM and healthy controls.53 De Simone and colleagues assessed
UCA isomers in the skin of patients with a past history of nonmelanoma skin cancer (NMSC, consisting of BCCs and squamous
cell carcinomas) at different times of the year.54 No significant
difference in total UCA or percentage as cis-UCA between patient
and control groups was found in either photoexposed (outer arm)
or non-photoexposed (buttock) sites in the winter period. In the
summer months, the percentage of cis-UCA in the photoexposed
site of the patients was considerably lower than in the controls
(17% vs. 42%) although it did not differ in the non-photoexposed
site. It is likely that this result does not reflect a risk factor for
subjects to develop skin cancer but merely reflects the fact that
people who have had skin cancer in the past are more likely to
avoid direct sun exposure in the summer than people in the control
group.
658 | Photochem. Photobiol. Sci., 2008, 7, 655–667
Thus the evidence to date indicates that people with a past
history of either CMM or NMSC do not differ from healthy
controls in their cutaneous UCA concentration, percentage as
cis-UCA or rate of photoisomerisation.
Mechanism of action of cis-UCA as an initiator of
UVR-induced immunosuppression
Following UVR of the skin, suppression of cell-mediated immunity is induced. The major chromophores, present in the upper
layers of the epidermis, that act as initiators of this process are
DNA, trans-UCA and membrane components. The pathway leading from the absorption of UVR photons by the chromophores to
the downregulation of T cell responses is complex and is shown
in outline in Fig. 2. Readers are referred to the comprehensive
reviews of Clydesdale et al.,55 Schwarz,56 Ullrich,57 Schade et al.,58
Hanneman et al.,59 and Norval60 for more details, and to Norval
and El-Ghorr for a description of methods to determine the
immunomodulatory effects of cis-UCA.61
Fig. 2 Outline of the pathway leading to suppression of cell-mediated
immunity as a result of exposure to ultraviolet radiation (UVR).
At the outset, it is clear that the mechanism of action of
cis-UCA as an immunosuppressive agent has not been fully
explained. Currently there is evidence for more than one pathway
and it is possible that cis-UCA may act on different cell types
found in various body sites in different ways. After the UVRinduced isomerisation of trans to cis-UCA in the stratum corneum,
cis-UCA persists in the epidermis of human subjects for at
least 2 weeks following the exposure, gradually returning to the
background level during that time.62 It is also found for several
This journal is © The Royal Society of Chemistry and Owner Societies 2008
weeks in suction blister fluid, presumably indicating that it is
present in the dermis.63 Some is released systemically as it has
been detected in serum for 1–2 days after UVR64 and is excreted in
the urine for about 2 weeks.65 Thus there is the opportunity for cisUCA to affect immune cell populations, not only in the epidermis
but also in the dermis, lymph nodes and even in the blood, spleen,
thymus or bone marrow.
To add to the complexity, not all types of antigens or immune
responses may be affected by cis-UCA similarly. El-Ghorr and
Norval66 irradiated mice with three UVR sources emitting various
wavebands, followed by tests of contact hypersensitivity (CHS)
and delayed type hypersensitivity (DTH) and by UCA analysis,
and found that there was no correlation between the suppression of
either hypersensitivity response and the concentration of cis-UCA
in the skin. Furthermore Kim et al.67 showed that the viability of
the antigen determined the differential contribution of cis-UCA
or DNA as initiators of UVR-induced suppression of DTH. Here
mice were UVR-irradiated and the importance of cis-UCA or
DNA damage assessed by injection of a monoclonal antibody with
specificity for cis-UCA or application of liposomes containing
DNA repair enzymes to the skin. Subsequent DTH tests with
live and either formalin-fixed or killed antigens revealed that cisUCA was the critical initiator molecule when live antigens were
used, whereas damaged DNA was the critical initiator when dead
antigens were used. The process by which cis-UCA affects the
ability of various populations of antigen presenting cells to process
live or dead antigens, together with their subsequent maturation
and cytokine production is largely unknown.
To provide clarity, the following sections deal separately with
five ways in which cis-UCA has been proposed to down-regulate
immunity. These are by occupying specific receptors, by altering
cytokine production, by affecting antigen presentation, by functional effects on nerve/mast cells, and by inhibiting the generation
of reactive oxygen species. Of course, in reality each of these mechanisms should not be considered singly, such as the occupation of
a receptor by cis-UCA which could have significant consequences
for the immune function of that cell type. A summary is provided
in Table 1 of the current possibilities whereby cis-UCA might
suppress cell-mediated immunity. It should also be noted that
cis-UCA can be immunotoxic. A single administration of cisUCA leads to decreased splenocyte phagocytosis in C57BL/6N
mice, while prolonged cis-UCA treatment (4 weeks) results in
thymic atrophy and hypocellularity and in splenic and lymph
node hypercellularity in both C57BL/6N and C3H/HeN strains
of mice.68,69 The mechanisms for these changes and any resulting
consequence for the immune response have not been investigated.
Cis-UCA receptors
Early experiments in mouse models demonstrated that histamine
receptor antagonists/agonists could reverse the ability of cisUCA to down-regulate DTH responses. However attempts to
show that cis-UCA acts through histamine-like receptors on
keratinocytes, monocytes or Langerhans cells have failed. Laihia
et al.70 analysed the binding of UCA isomers to histamine H1 , H2
and H3 receptors and, because of the structural similarities of UCA
with c-aminobutyric acid (GABA), to the GABA receptors also,
on rat cortex membranes. While competitive binding curves did
not provide evidence that histamine receptors for cis-UCA were
Table 1 Summary of possible pathways by which cis-urocanic acid
suppresses cell-mediated and innate immunity
Mechanism
Details
Through receptors
GABAA on cortical cells.70,71
Serotonin (5-HT2A ) on
unidentified cell type(s).74
Through cytokines and other
immune mediators
Prostaglandin E2 production by
keratinocytes in the presence of
histamine.86
Cytokine production by
human keratinocytes.85
IL-10 production by
activated CD4+ T cells.87
Through antigen presenting
cells
Impairment in antigen presentation
by epidermal cells; reversal by IL-12.90
Through nerve/mast cells
Stimulation of neuropeptides
(substance P, CGRP) from peripheral
sensory nerves, degranulation of mast
cells.73,92,93
Through neutrophils
Impairment in the generation of
extracellular reactive oxygen
species.96,97
present, both UCA isomers bound to GABAA receptors. Some
stereospecificity was involved as cis-UCA displaced [3 H]-GABA
by 48% and trans-UCA by 19%. Further experiments showed that
both isomers were more potent at pH 5.5, the pH of the skin, than
at pH 7.4, and that cis-UCA inhibited GABA responses, while
trans-UCA slightly enhanced them.71 While both isomers acted
with low potency on the GABAA receptors, it was noted that the
UCA concentration in the skin is high, ranging from about 2 to
62 nmol cm−2 in human epidermis.41,72 This is similar to the range
that was used experimentally.
As various neuropeptides have been implicated as mediators in
UVR-induced immunosuppression and as GABA is an inhibitory
neurotransmitter, it was suggested that cis-UCA could bind to
the GABAA receptor, thus encouraging the secretion of various
cutaneous mediators, such as histamine and prostaglandins, that
down-regulate local immune responses. However GABA receptors
have not been located in the skin, although they are present on
T cells, and they are not generally found on peripheral nerves.
In addition Khalil et al.73 showed that cis-UCA could stimulate
neuropeptide release from peripheral sensory nerves while GABA
did not. Therefore, for all these reasons, it seems unlikely that cisUCA acts through the GABA receptors to initiate the suppression
of cell-mediated immunity.
Significant progress has been made recently with the discovery
that cis-UCA may act via the serotonin, 5-hydroxytryptamine (5HT) receptor.74 The ring-like structure that cis-UCA forms in
aqueous solution resembles the structure of 5-HT (see Fig. 3).
A series of careful experiments showed first that cis-UCA bound
to this receptor with relatively high affinity while trans-UCA did
not. Treatment with a selective serotonin antagonist blocked the
binding of cis-UCA, and 5-HT acted as a competitive inhibitor for
the binding of cis-UCA. Secondly cis-UCA, but not trans-UCA,
was demonstrated to mobilise intracellular calcium stores within
cells expressing serotonin receptors, implying that it did this by
engaging the serotonin receptor. Thirdly in vivo experiments were
This journal is © The Royal Society of Chemistry and Owner Societies 2008
Photochem. Photobiol. Sci., 2008, 7, 655–667 | 659
Fig. 3 The structures of cis-urocanic acid and serotonin, illustrating their
similarities.
set up in which mice were UVR-irradiated or were treated with
cis-UCA or serotonin. They were then immunised with formalinfixed Candida albicans and the DTH assessed subsequently by
intradermal injection of C. albicans. All these procedures resulted
in suppression of the DTH response compared with untreated
mice. However if the mice were injected with an anti-cis-UCA
antibody or an anti-5-HT antibody prior to the UVR exposure,
cis-UCA or 5-HT administration, the immunosuppression was
blocked. Tests using a series of serotonin receptor agonists and
antagonists with specificity for various 5-HT receptor subtypes
revealed that cis-UCA activated the 5-HT2A receptor to suppress
DTH.
The cell target expressing the 5-HT2A receptors and its site in the
body are not yet known. Such receptors are found on dendritic
cells,75 on T and B cells,76 on nerve cells77 and on mast cells.78
Each of these cell types has been implicated in UVR-induced
immunosuppression, as described in the sections below. Finally,
it should be noted that results presented recently by Woodward
et al.79 did not confirm that cis-UCA acts through the 5-HT2A
receptor. Here human peripheral blood mononuclear cells were
stimulated in vitro with lipopolysaccharide in the presence of cisUCA or serotonin, and the production of TNF-a monitored.
Both cis-UCA and serotonin suppressed TNF-a release but the
down-regulating effect of cis-UCA was abrogated by adding
indomethacin (an inhibitor of prostaglandin production) to the
cultures; in contrast, the down-regulating effect of serotonin was
not abrogated. Similarly, when the production of prostaglandin
E2 in the cultures was measured, cis-UCA induced it in a
dose-dependent manner but serotonin was only effective at a
supraphysiological concentration. The test system used here was
an artificial one, relying on the in vitro response of the peripheral
blood mononuclear cells alone, and as such is unlikely to mimic
what happens in vivo, particularly locally in the skin. In addition
the secretion of cytokines by monocytes is known to be suppressed
by 5-HT2A receptor binding, rather than being activated.80
Cytokines and other immune mediators
While broadband UVB is known to induce a variety of cytokines
such as TNF-a and TGF-b, and other immune mediators such as
platelet activating factor, prostaglandins and histamine, in the skin
and systemically, the consequences of cis-UCA application are less
clear. An early hypothesis, proposed by Kurimoto and Streilein,81
was that cis-UCA acts on keratinocytes to induce the production of
TNF-a. However cis-UCA treatment of the murine keratinocyte
cell line, PAM-212, failed to cause any detectable change in the
mRNA or protein expression of the immunosuppressive cytokines
TNF-a, IL-10 and TGF-b.82 In addition, studies in knock-out
mice that were deficient in TNF receptor 1 and 2 showed that
cis-UCA is still capable of suppressing both local and systemic
660 | Photochem. Photobiol. Sci., 2008, 7, 655–667
CHS, as it did in the wild-type mice.83,84 Thus these results indicate
that TNF-a signalling is unlikely to play a major part in the
mechanism of action of cis-UCA although it should be noted
that the response of human keratinocytes may be different from
that in mice. Kaneko et al.85 have demonstrated very recently
that cis-UCA induces the production of several cytokine proteins,
including TNF-a, in primary human keratinocytes. In addition
prostaglandin-endoperoxide synthase 2 is highly up-regulated by
cis-UCA, resulting in an enhanced secretion of prostaglandin
E2 into the culture supernatant. Previously it has been shown
that cis-UCA can act in synergy with histamine to induce the
production of prostaglandin E2 from human keratinocytes in
vitro.86 Whether these mechanisms involving immune mediators
produced by keratinocytes are of importance in vivo remains to be
established.
An interesting report investigated the down-regulating effects
of cis-UCA on the ability of mouse spleen cells to act as antigen
presenting cells.87 It was shown that the reason for the suppression
in antigen presentation was due to the stimulation of IL-10
production by activated CD4+ T cells. The main target for cis-UCA
was shown to be this cell population and not the macrophages
or any other cell type present in the spleen. The increase in
IL-10 could then lead to inhibition of antigen presentation by
dendritic cells, affect the production of T regulatory cells and
down-regulate the T helper 1 response.87 These findings have
not been corroborated, as far as we are aware, but it would be
worthwhile to undertake further investigations using the reagents
that are available currently to phenotype the CD4 cell population
in the spleen that responds to cis-UCA by producing IL-10.
In particular any interaction with T regulatory cells could be
important in helping to explain how cis-UCA acts.
Antigen presentation
While it is an attractive concept that cis-UCA could affect the ability of Langerhans cells or dendritic cells to present antigen, such an
effect has not been demonstrated in in vitro studies. For example,
cis-UCA did not change the development of dendritic cells derived
from bone marrow or their allo-antigen presenting capability.88 In
addition cis-UCA does not alter the expression of MHC Class
II or the co-stimulatory molecules required for effective antigen
presentation.88,89 In contrast Beissert et al.90 have developed a
mouse tumour model in which a suspension of epidermal cells
(containing 5–15% Langerhans cells) were first pulsed ex vivo with
a tumour-associated antigen, derived from a spindle cell line. The
cells were then injected into the mice to immunise them, and the
animals were challenged subsequently with the spindle cells to
find out if they had been protected, as demonstrated by rejection
of the tumour. Under normal circumstances, they were but, if
the incubation of the epidermal cells with the tumour-associated
antigen had taken place in the presence of cis-UCA, the protective
effect was lost. It was concluded that cis-UCA had down-regulated
the ability of the epidermal cells to present the tumour antigen,
thus failing to immunise the mice. Further investigation revealed
that, if the epidermal cells were incubated ex vivo with cis-UCA in
the presence of IL-12, then the suppression in the protective effect
was prevented.90 IL-12 treatment also abrogated the suppression
in CHS responses induced by cis-UCA in mice. Finally incubation
of the epidermal cells in the presence of cis-UCA with an antigen
This journal is © The Royal Society of Chemistry and Owner Societies 2008
that required processing before presentation, and another antigen
that did not require processing before presentation, showed that
cis-UCA acted mainly by impairing antigen presentation.90
These data indicate that cis-UCA may down-regulate antigen
presentation and that IL-12 can protect against this effect, perhaps
by inhibiting the apoptosis induced by T regulatory cells.91 It
should be noted that the epidermal cell population used in the
above experiments, although enriched for I-A+ cells, was not pure
and an interaction of cis-UCA with other cell populations is
certainly possible.
Nerve/mast cells
The first indication that cis-UCA might target mast cells came
from studies in mast cell-deficient mice. It was shown that they
were resistant to suppression of the CHS response, induced by cisUCA.92 If their dorsal skin was reconstituted with bone-marrow
derived-mast cell precursors, the mice became susceptible to the
immunomodulating effects of cis-UCA. In 1999 Wille et al.93 used
human skin organ cultures treated with cis-UCA and showed
that mast cell chymase was depleted and TNF-a was produced,
demonstrating that cis-UCA had induced mast cell degranulation.
More recently it has been revealed that the effect of cis-UCA
on mast cells is more likely to be indirect, via the stimulation
of neuropeptides from peripheral sensory nerves. Khalil et al.73
induced a blister on the hind footpad of rats and, following
removal of the surface epithelium, perfused the area with cis-UCA,
trans-UCA and other molecules. Cis-UCA, but not trans-UCA,
increased the microvascular flow and this was due to neuropeptide
release. Substance P and calcitonin gene related peptide (CGRP)
were responsible for most of the cis-UCA-induced change in flow.
Furthermore, in mice treated with capsaicin to deplete sensory
neuropeptides, cis-UCA did not suppress CHS responses. It was
concluded that cis-UCA acts first on the peripheral terminals
of unmyelinated primary sensory nerves leading to production
of neuropeptides, and that these, in turn, degranulate the mast
cells. The products of the mast cells, particularly histamine, lead
to stimulation of prostaglandin synthesis by keratinocytes and
ultimately suppression of cell-mediated immunity by this route.
The neuropeptides themselves can also be down-regulatory. For
example, CGRP can bind to Langerhans cells and induce IL10 production,94 and substance P can bind to keratinocytes
and stimulate IL-1 production.95 Equivalent studies to determine
whether cis-UCA alters neuropeptide production in human skin
have not been undertaken.
Generation of reactive oxygen species by neutrophils
Polymorphonuclear neutrophils provide an essential contribution
to innate immunity. They are recruited to the site of an infection
and, on activation, engulf and kill the microbial pathogens. This
process is dependent on the production of microbicidal peptides,
proteases and reactive oxygen species (ROS), also referred to
as respiratory or oxidative burst activity. Kivisto et al.96 have
shown in an in vitro study that the respiratory burst activity
of human neutrophils can be inhibited by cis-UCA. Further
investigation has revealed that cis-UCA suppresses the generation
of extracellular superoxide by neutrophils while not affecting the
generation of intracellular superoxide or other ROS.97 Phagocytic
and bactericidal activities were also not altered by cis-UCA. The
mechanism involved and whether the interactions take place
outside or inside the neutrophils have not been elucidated.
These interesting results suggest that cis-UCA may have some
therapeutic potential in situations where there is recruitment of
large numbers of neutrophils as it could limit the production of
extracellular ROS that damage the host tissues whilst preserving
the activities required for microbial clearance.97
Role of cis-UCA in infectious diseases
Exposure to UVB is known to suppress cell-mediated immune
responses to a variety of infectious agents in mouse and rat
models. Similar results have been obtained when the UVR is
replaced by cis-UCA. For example, rats were infected orally
with the parasitic worm, Trichinella spiralis, and then injected
subcutaneously with a range of doses of cis or trans-UCA.98 The
number of T. spiralis larvae in the muscle tissue was increased in the
animals treated with cis-UCA compared with those treated with
trans-UCA. In addition the DTH response to T. spiralis antigens
was significantly suppressed by the cis-UCA treatment. If the rats
were injected with an anti-cis-UCA antibody before being UVirradiated and infected with T. spiralis, the expected increase in
larvae counts and downregulation in DTH were abrogated. Thus,
in this model, cis-UCA is proved to be an important mediator of
UVB-induced suppression of cell-mediated immunity. A study in a
hairless guinea-pig model of Buruli ulcer disease reached the same
conclusion.99 The disease, characterised by the development of
chronic necrotising skin ulcers with an associated social stigma, is
caused by an extracellular infection with Mycobacterium ulcerans.
The animals were treated topically for 3 consecutive days with
trans-UCA or a mixture of 1:9 cis:trans-UCA or vehicle. They
were infected intradermally with M. ulcerans and the resultant skin
lesions measured, together with the DTH response to M. ulcerans
cell fragment antigens. Compared with the guinea-pigs treated
with trans-UCA or vehicle, the animals treated with the UCA
mixture developed more severe skin lesions and had suppressed
DTH responses. These results indicate that cis-UCA enhances the
ulcerative form of M. ulcerans disease.
There is also evidence that cis-UCA can suppress the cellmediated immune response to viruses. Sleijffers et al.100 irradiated
volunteers with one personal MED on each of 5 consecutive days.
They were then vaccinated with hepatitis B surface antigen. The
UCA isomer levels in the skin were assayed before and immediately
after the UV exposure, and the in vitro lymphocyte response to
various mitogens, recall antigens such as tetanus and diphtheria,
and hepatitis B virus was also measured before and at several time
points after UV exposure and vaccination. It was found that the
subjects with a higher cis-UCA concentration after UV exposure
had slightly lowered hepatitis B-specific lymphocyte responses. It
is not known if this rather small (although statistically significant)
difference in the T cell response due to cis-UCA content would lead
to an actual reduced level of protection against a future hepatitis
B infection, but this was thought unlikely by the authors. No
such correlation was apparent between cis-UCA levels and the
other lymphocyte responses tested, nor between cis-UCA levels
and hepatitis B-specific antibody titres.
While there is some evidence to support a role for UVA in
UV-induced immunosuppression,101 Reeve et al.102 have shown
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Photochem. Photobiol. Sci., 2008, 7, 655–667 | 661
the reverse-that UVA can protect against UVB-induced immunosuppression. It has been suggested that this effect could be
mediated through cis-UCA. One model of infection to support
this view has been studied. Pre-exposure of mice to UVA before UVB irradiation or cis-UCA treatment and infection with
Listeria monocytogenes resulted in a reversal of the expected
down-regulation in the cell-mediated immune response to the
bacterium.103 The reader is referred to the ‘Protection against the
immunosuppressive effects of cis-UCA’ section below for further
details.
The elegant studies of Safer et al.104 demonstrate that UCA
is a major chemoattractant for the skin-penetrating nematode,
Strongyloides stercoralis. Although Safer et al. did not determine
the isomer content of the UCA used in their experiments, it is likely
to be trans-UCA. If the chemoattractant properties of UCA are
isomer-specific, there may be some potential to reduce infection
with S. stercoralis by exposing the skin to solar UVR so that about
half of the UCA is converted to the cis-isomer. As S. stercoralis
is a soil-dwelling parasite, most commonly infecting via the soles
of the feet, such an activity may require an unusual sunbathing
position!
Role of cis-UCA in photocarcinogenesis
It is well established that topical application of UCA increases
both the incidence and malignancy of UVR-induced skin cancers
in a hairless mouse model.105 The hypothesis tested in this work was
that increased levels of cutaneous UCA would lead to increased
cis-UCA after UV exposure, thus enhancing photoimmunosuppression and increasing oncogenicity. This approach, however,
does not mirror the natural situation as extra UCA was applied
externally. In addition, as outlined in the ‘Photoisomerisation of
UCA’ section above, there is no experimental evidence to date
showing that individuals with a past history of skin cancer differ
from healthy individuals in their total cutaneous UCA concentration or percentage as cis-UCA or rate of isomerisation from
trans to cis-UCA on UV exposure.52–54 These studies contained
subjects with phototype I-IV but none with phototype V or
VI. An interesting suggestion in this context has been made
by Hug106 that differing levels of epidermal UCA may explain
the observation that black women with a previous NMSC are
at more than three-fold increased relative risk of developing a
further NMSC compared with white women.107 Quoting two
reports in which the UCA content of black skin is found to be
more than three times higher than in white skin, Hug argues that
this may render black individuals more susceptible to increased
photoimmunosuppression and thus to be at higher risk of NMSC
development.
The most convincing experimental evidence to date that endogenous cis-UCA plays an important role in photocarcinogenesis
comes from the study of Beissert et al. in mice.80 The animals were
irradiated with increasing doses of UVB over a period of 6 months
and then observed for the development of skin tumours over
the next 6 months. One group was treated with an anti-cis-UCA
antibody, administered intraperitoneally before each exposure and
two control groups contained mice that were only UV-irradiated,
or were treated with an irrelevant isotype-matched antibody before
each exposure. All the animals in both control groups developed
tumours after 182 days but, in contrast, after 200 days, only 50%
662 | Photochem. Photobiol. Sci., 2008, 7, 655–667
of the animals in the anti-cis-UCA antibody treated group had
developed tumours. Thus cis-UCA is involved in UV-induced
skin cancer in mice and, as outlined in the ‘Antigen presentation’
section above, may act to inhibit antigen presentation, an effect
that can be reversed by IL-12.80 It is not known at what point
or points the down-regulation might happen. To try to address
this issue, another study used a line of fibrosarcoma cells (FSA)
which, when implanted subcutaneously into mice, grew into skin
tumours.108 Cis-UCA applied topically or intradermally for three
weeks before the injection of FSA cells had no effect on tumour
outgrowth, while prior UVB irradiation enhanced the outgrowth
considerably. In confirmation, treatment with an anti-cis-UCA
antibody before each UVB exposure did not inhibit the increased
growth of the tumours compared with unirradiated animals. This
result was taken as evidence that UV-enhanced growth of skin
tumours is not mediated by cis-UCA, and therefore that cis-UCA
is more likely to act at an early stage of UV-induced carcinogenesis
rather than at a later progression stage.
Protection against the immunosuppressive effects of
cis-UCA
UVR production of cis-UCA occurs via the singlet state of transUCA in the upper layers of the human epidermis. Strategies to protect against cis-UCA production are therefore very much restricted
to limiting those UVR wavelengths responsible for maximum
trans-UCA singlet formation reaching the skin. All sunscreens, if
applied correctly, are likely to protect to some degree against both
erythema and cis-UCA production.109 However, protection against
these two UVR effects are highly wavelength dependent. As
detailed above (see ‘Photochemistry of UCA’ section), the action
spectrum for cis-UCA production is red-shifted from both the
trans-UCA absorption spectrum and the UVR erythemal action
spectrum in human skin.7 This explains why a predominantly UVB
sunscreen might protect efficiently against erythema but be less
protective against cis-UCA production.110 Also it may provide
a reason for the discrepancy between the sun protection factor
and the immune protection factor noted with UVB sunscreens
which is not so apparent with broad spectrum (UVB and UVA)
sunscreens.111,112 Interestingly, in mice, it has been shown that two
UVB sunscreens, 2-ethylhexyl-p-methoxycinnamate (2-EHMC)
and octyl-N-dimethyl-p-aminobenzoate (o-PABA), both fail to
protect against UVR-induced cis-UCA production, but 2-EHMC
is highly effective at protecting against UVR-induced suppression
of CHS.113 Further study revealed that 2-EHMC also abrogates
immunosuppression induced by topical cis-UCA in the absence of
UVR, suggesting that a ‘neutralising’ chemical reaction may occur
between 2-EHMC and cis-UCA.113 Paradoxically, the physical
sunscreen, titanium dioxide, may reduce the production of cisUCA109 but can also photosensitise UVA-induced trans-UCA
oxidation in vitro.114 The latter effect could result in increased
levels of the immunosuppressive photooxidation products.30
Several studies in mice have investigated strategies to protect
against the immunosuppressive effects of exogenously applied cisUCA. When applied topically, the omega-3 fatty acid, eicosapentaenoic acid (EPA), effectively inhibits UVB and topical cis-UCAinduced suppression of CHS responses.115 The mechanisms for
this effect are not clear but are likely to be linked to either the
This journal is © The Royal Society of Chemistry and Owner Societies 2008
antioxidant properties of EPA or its ability to compete with
omega-6 fatty acid cyclooxygenase substrates (e.g. arachadonic
acid), thus reducing the production of immunosuppressive
prostaglandin E2 .115 PycnogenolR , an antioxidant extracted from
the bark of the French maritime pine, Pinus pinaster Ait., abrogates
inhibition of CHS by UVR and by cis-UCA when applied
to the skin immediately after either treatment.116 Significantly
PycnogenolR also protects against photocarcinogenesis if applied
after each daily irradiation, thus providing indirect evidence for
the involvement of cis-UCA in this process.116
Certain isoflavonoids such as the genistein metabolite, [S]-4 7dihydroxyisoflavane (equol), extracted from red clover (Trifolium
pratense) have radical scavenging properties, induce the cutaneous
antioxidant metallothionein and are also phytoestrogens that bind
efficiently to estrogen receptors (ER). In mice, topical equol
partially reverses the suppression in CHS induced by UVR or
by topically applied cis-UCA.117 Recent studies have indicated
the mechanisms by which this may occur. Using metallothioneinknockout mice, it was clear that metallothionein protects against
immunosuppression produced by either UVR or cis-UCA.118 In
the same mouse model it was demonstrated that equol protection
against both agents is also partially dependent on metallothionein
production.119 Further studies using an ER antagonist suggest
that the phytoestrogenic property of equol plays a role in reducing
both UVR and cis-UCA-induced immunosuppression via an
ER-dependent upregulation of metallothionein.120 Interestingly,
17-b-estradiol also abrogated both UVR and cis-UCA-induced
suppression of CHS. This suggests a gender specific susceptibility
that may relate to epidemiological and experimental results
showing a lower risk of skin cancer in females compared with
males.121,122
As mentioned above (see ‘Role of cis-UCA in infectious diseases’
section) prior or concurrent exposure of mouse skin to UVA is
reported to reduce immunosuppression caused by either UVB
or cis-UCA.102 This UVA protective effect is dependent on the
induction of the cutaneous stress-protein, haem oxygenase-1
(HO-1) and can be reduced by tin protoporphyrin, a specific
HO-1 inhibitor.123 As a product of its haem catabolic activity,
HO-1 releases carbon monoxide (CO) and studies with specific CO generating systems suggest that it is CO generated
by HO-1 activity that abrogates UVB and cis-UCA-induced
immunosuppression.124 Further experiments have demonstrated
that UVA immunoprotection is dependent on CO binding to
cutaneous guanylyl cyclase (GC) and the consequent production
of cyclic guanosine monophosphate (cGMP). Treatment of mice
with sildenafil (ViagraR ) which inhibits cGMP degradation has
the same effect as CO binding.125
Whilst the primary aim of the above studies has been to identify
candidate targets to protect against photoimmunosuppression,
they have also increased the understanding of how cis-UCA may
mediate its immunomodulatory effects.
Conclusions
Significant progress has been made in recent years towards a fuller
knowledge of the photochemistry and photobiology of UCA,
although much remains to be discovered.
An understanding of the complex primary photoprocesses that
contribute to the wavelength dependence of the quantum yield
for trans-UCA photoisomerisation has explained why the action
spectrum for cis-UCA production is red-shifted from the transUCA absorption spectrum. The original argument linking transUCA photoisomerisation to photoimmunosuppression was based
on the similarity of the trans-UCA absorption spectrum and the
action spectrum for suppression of CHS. Now we know why the
red-shift occurs, it is necessary to investigate other chromophores
and photoproducts of trans-UCA to assess the relative contribution of cis-UCA production in photoimmunosuppression.
From the studies discussed above, it is clear that the oxidative
breakdown of trans-UCA may produce photoproducts that are
as immunosuppressive as cis-UCA but whose photochemistry
is largely unexplored. The photosensitising properties of the
triplet state of trans-UCA and its interactions with biomolecules
(particularly structural proteins which share a common location
and are important in skin terminal differentiation) require further
investigation. The contrasting abilities of trans-UCA to both
photosensitise and scavenge ROS and other radical species also
need to be explored more fully in relation to immunosuppression.
The analyses of the concentration of UCA in human skin have
revealed large differences between individuals that have failed to
be related to any other biological parameter. It would be useful to
measure histidine concentration as well as UCA isomers in future
skin samples as the former may affect the latter. In addition the
ability to assess histamine concentration in the skin of healthy
subjects and those with various dermatoses would be interesting
because histamine is formed in one step from histidine, as is
trans-UCA, and it is an important cutaneous immune mediator
following UVR. Although experiments in mice indicate that cisUCA suppresses hypersensitivity response dose-dependently, the
range of cis-UCA doses used was limited. In humans, preliminary
results demonstrate that fair-skinned people may be at relatively
higher risk of immunosuppression following suberythemal UVB
exposure, due to a higher rate of isomerisation to cis-UCA,
compared with more pigmented people. In addition a high UCA
level may lead to the production of more DNA photoproducts
and an increased chance of a downregulated antigen-specific T
cell response. However individuals with a history of skin cancer,
where past exposure to solar UVR is recognised as a major risk
factor, do not have a different cutaneous UCA content, percentage
as cis-UCA or rate of isomerisation from trans to cis-UCA from
individuals without a history of skin cancer. This argues against a
critical role for cis-UCA in human photocarcinogenesis, although
experiments in mice have shown that inhibiting the action of cisUCA provides partial protection against the generation of skin
tumours. As the percentage of cis-UCA is at the maximum possible
in most body sites during the summer months (at mid-latitudes),
this means that there is no adaptation in UCA concentration or
in the ratio of UCA isomers over an extended period of time as a
result of repeated solar UVR.
Cis-UCA is recognised as an important initiator of the complex
cascade leading to suppression of cell-mediated immunity, but
its mechanism of action is still not clear, despite many different
approaches being taken. It is likely that it has more than one
immunological effect, and may act not only locally in the skin
where it is formed but also systemically. Recent results indicate that
the 5-HT2A receptor is involved and it will be important to identify
the cell target that expresses this receptor and where it is located.
Evidence demonstrating that cis-UCA induces the production of
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Photochem. Photobiol. Sci., 2008, 7, 655–667 | 663
IL-10 by activated CD4+ T cells requires corroboration and also
an identification of the subtype of CD4+ cell involved, particularly
to find out if it could be classified as a T regulatory cell. Other
data show that cis-UCA has an inhibitory effect on antigen
presentation, a process that can be reversed by IL-12, and that
it can indirectly target mast cells by stimulating the generation of
neuropeptides from peripheral sensory nerves that then lead to the
degranulation of the mast cells.
The degree to which we wish to protect against UCA-mediated
photoimmunosuppression needs to be debated fully. On the one
hand reduced immunosuppression may reduce skin cancer risk
but at the same time increase the incidence of immunological
photodermatoses. In common with the majority of the research
discussed in this review, the studies on protection against cis-UCAinduced immunosuppression have been conducted in mice and
have revealed tantalising mechanistic pathways. Methodologies
for studying clinical photoimmunology have improved dramatically over the last ten years and it is now time to explore these
UCA pathways in human subjects.
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