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• W2064553763 abstract "Urocanic acid (UCA) is present at millimolar concentrations in mammalian epidermis and undergoes photoisomerization from the naturally occurring trans-isomer to the cis-isomer on exposure to ultraviolet radiation (UVR). Cis-UCA causes downregulation of various immune responses in mouse and human experimental models and has been proposed as both a chromophore and a mediator of UV-induced immune suppression. In this study, the wavelength dependence from 260–340 nm for trans to cis-UCA photoisomerization in human skin was analyzed in five healthy volunteers. The resulting action spectrum demonstrated maximal cis-UCA production in the UVB spectral region of 280–310 nm. This spectral peak is red-shifted to longer wavelengths compared with the erythemal action spectrum. The cis-UCA action spectrum can be used to predict the ability of sunscreens to protect against UVR-induced cis-UCA formation and may assist in explaining discrepancies between sunscreens' abilities to protect against erythema and photoimmunosuppression. Urocanic acid (UCA) is present at millimolar concentrations in mammalian epidermis and undergoes photoisomerization from the naturally occurring trans-isomer to the cis-isomer on exposure to ultraviolet radiation (UVR). Cis-UCA causes downregulation of various immune responses in mouse and human experimental models and has been proposed as both a chromophore and a mediator of UV-induced immune suppression. In this study, the wavelength dependence from 260–340 nm for trans to cis-UCA photoisomerization in human skin was analyzed in five healthy volunteers. The resulting action spectrum demonstrated maximal cis-UCA production in the UVB spectral region of 280–310 nm. This spectral peak is red-shifted to longer wavelengths compared with the erythemal action spectrum. The cis-UCA action spectrum can be used to predict the ability of sunscreens to protect against UVR-induced cis-UCA formation and may assist in explaining discrepancies between sunscreens' abilities to protect against erythema and photoimmunosuppression. urocanic acid ultraviolet radiation Ultraviolet radiation (UVR) exposure of human and rodent skin suppresses cell-mediated immune responses (Fisher and Kripke, 1977Fisher M.S. Kripke M.L. Systemic alteration induced in mice by ultraviolet radiation and its relationship to ultraviolet carcinogenesis.Proc Natl Acad Sci USA. 1977; 74: 1688-1692Crossref PubMed Scopus (363) Google Scholar; Schwarz, 2002Schwarz T. Photoimmunosuppression.Photodermatol Photoimmunol Photomed. 2002; 18: 141-145Crossref PubMed Scopus (77) Google Scholar). This photoimmunosuppression decreases resistance to tumor cells and microbial infections (Duthie et al., 1999Duthie M.S. Kimber I. Norval M. The effects of ultraviolet radiation on the human immune system.Br J Dermatol. 1999; 140: 995-1009Crossref PubMed Scopus (195) Google Scholar). The skin chromophores responsible for initiating photoimmunosuppression are not fully defined but there is considerable evidence that DNA (Vink et al., 1996Vink A.A. Yarosh D.B. Kripke M.L. Chromophore for UV-induced immunosuppression: DNA.Photochem Photobiol. 1996; 63: 383-386Crossref PubMed Scopus (53) Google Scholar; Nghiem et al., 2002Nghiem D.X. Kazimi N. Mitchell D.L. Vink A.A. Ananthaswamy H.N. Kripke M.L. Ullrich S.E. Mechanisms underlying the suppression of established immune responses by ultraviolet radiation.J Invest Dermatol. 2002; 119: 600-608Crossref PubMed Scopus (76) Google Scholar) and urocanic acid (UCA; (2-propanoic acid, 3-[imidazol-4 (5)-yl]) (Kim et al., 2003Kim T.H. Moodycliffe A.M. Yarosh D.B. Norval M. Kripke M.L. Ullrich S.E. Viability of the antigen determines whether DNA or urocanic acid act as initiator molecules for UV-induced suppression of delayed-type hypersensitivity.Photochem Photobiol. 2003; 78: 228-234Crossref PubMed Scopus (17) Google Scholar) are candidates. UCA is present as trans-UCA in the stratum corneum of human skin in high (mM) concentrations (Kavanagh et al., 1995Kavanagh G. Crosby J. Norval M. Urocanic acid isomers in human skin: Analysis of site variation.Br J Dermatol. 1995; 133: 728-731Crossref PubMed Scopus (39) Google Scholar). On exposure to UVR, trans-UCA is photoisomerized to cis-UCA (Edlbacher and Hertz, 1943Edlbacher S. Hertz F. Urocanic acid.Z Physiol Chem. 1943; 279: 63-65Crossref Scopus (12) Google Scholar). Photoisomerization of trans-UCA increases in a UVR dose-dependent fashion until a “photostationary” level is reached at approximately 60%cis-UCA. The original proposal that trans-UCA may be the chromophore for photoimmunosuppression was made byDe Fabo and Noonan, 1983De Fabo E.C. Noonan F.P. Mechanisms of immune suppression by ultraviolet irradiation in vivo. I. Evidence for the existence of a unique photoreceptor in the skin and its role in photoimmunology.J Exp Med. 1983; 157: 84-98Crossref Scopus (452) Google Scholar who demonstrated that the UVR wavelength dependence (action spectrum) for suppression of contact hypersensitivity (CHS) in mice peaked at 260–270 nm and was super-imposable on the absorption spectrum of trans-UCA. When the trans-UCA-containing stratum corneum was removed by tape stripping, the mice became refractory to photoimmunosuppression (De Fabo and Noonan, 1983De Fabo E.C. Noonan F.P. Mechanisms of immune suppression by ultraviolet irradiation in vivo. I. Evidence for the existence of a unique photoreceptor in the skin and its role in photoimmunology.J Exp Med. 1983; 157: 84-98Crossref Scopus (452) Google Scholar). Subsequent studies have demonstrated that cis-UCA can suppress contact and delayed type hypersensitivity, resistance to infectious diseases, skin and other allograft rejection, and graft-versus-host disease in rodents (Norval and El-Ghorr, 2002Norval M. El-Ghorr A.A. Studies to determine the immunomodulating effects of cis-urocanic acid.Methods. 2002; 28: 63-70Crossref PubMed Scopus (32) Google Scholar). Cis-UCA also increases the risk of non-melanoma skin cancer in mouse models (Reeve et al., 1989Reeve V.E. Greenoak G.E. Canfield P.J. Boehm-Wilcox C. Gallagher C.H. Topical urocanic acid enhances UV-induced tumour yield and malignancy in the hairless mouse.Photochem Photobiol. 1989; 49: 459-464Crossref PubMed Scopus (79) Google Scholar; Beissert et al., 2001Beissert S. Ruhlemann D. Mohammad T. et al.IL-12 prevents the inhibitory effects of cis-urocanic acid on tumor antigen presentation by Langerhans cells: Implications for photocarcinogenesis.J Immunol. 2001; 167: 6232-6238Crossref PubMed Scopus (70) Google Scholar). The immunosuppressive properties of UCA in human subjects have not been studied in vivo but in vitro experiments indicate that cis-UCA can suppress natural killer cell activity (Gilmour et al., 1993Gilmour J.W. Vestey J.P. George S. Norval M. Effect of phototherapy and urocanic acid isomers on natural killer cell function.J Invest Dermatol. 1993; 101: 169-174Abstract Full Text PDF PubMed Google Scholar), suppress antigen presenting function (Hurks et al., 1997Hurks M.H.M. Out-Luiting C. Van den Molen R.G. Vermeer B.J. Claas F.H. Mommaas A.M. Differential suppression of the human mixed epidermal cell lymphocyte reaction (MECLR) and mixed lymphocyte reaction (MLR) by cis-urocanic acid.Photochem Photobiol. 1997; 65: 616-621Crossref PubMed Scopus (12) Google Scholar), stimulate PGE2 production by mononuclear cells (Hart et al., 1993Hart P.H. Jones C.A. Jones K.L. Watson C.J. Santucci I. Spencer L.K. Finlay-Jones J.J. Cis-urocanic acid stimulates human peripheral blood monocyte prostaglandin E2 production and suppresses indirectly tumour necrosis factor-α.J Immunol. 1993; 150: 4514-4523PubMed Google Scholar) and keratinocytes (Jaksic et al., 1995Jaksic A. Finlay-Jones J.J. Watson C.J. Spencer L.K. Santucci I. Hart P.H. Cis-urocanic acid synergizes with histamine for increased PGE2 production by human keratinocytes: Link to indomethacin-inhibitable UVB-induced immunosuppression.Photochem Photobiol. 1995; 61: 303-309Crossref PubMed Scopus (80) Google Scholar), and suppress HLA-DR, IL-1β, IL-2, TNFα, and IL-1β production by mononuclear cells (Rasanen et al., 1989Rasanen L. Jansen C.T. Hyoty H. Reunala T. Morrison H. Cis-urocanic acid stereospecifically modulates human monocyte IL-1 production and surface HLA-DR antigen expression, T-cell IL-2 production and CD4/CD8 ratio.Photodermatology. 1989; 6: 287-292PubMed Google Scholar; Hart et al., 1993Hart P.H. Jones C.A. Jones K.L. Watson C.J. Santucci I. Spencer L.K. Finlay-Jones J.J. Cis-urocanic acid stimulates human peripheral blood monocyte prostaglandin E2 production and suppresses indirectly tumour necrosis factor-α.J Immunol. 1993; 150: 4514-4523PubMed Google Scholar; Laihia et al., 1994Laihia J.K. Jansen C.T. Uksila J. Punnonen J. Neuvonen K. Pasanen P. Ayras P. Effects of cis- and trans-urocanic acids on the secretion on interleukin-1β and tumour necrosis factor-α by human peripheral blood monocytes.Acta Derm Venereol (Stockh). 1994; 74: 266-268PubMed Google Scholar). In vivo, the critical event is the production of immunosuppressive cis-UCA from trans-UCA by photoisomerization. At a particular wavelength, the yield of cis-UCA is dependent on absorption by trans-UCA (peak absorption at ∼270 nm) and the quantum yield for the photoisomerization reaction. As work byMorrison et al., 1984Morrison H. Bernasconi A. Pandey G. A wavelength effect on urocanic acid e/z photoisomerisation.Photochem Photobiol. 1984; 40: 549-550Crossref PubMed Scopus (66) Google Scholar had demonstrated that the quantum yields for trans- to cis-UCA photoisomerization in vitro are wavelength dependent, there was a high probability that the action spectrum (wavelength dependence) for the reaction would not match the absorption spectrum of trans-UCA.Gibbs et al., 1993Gibbs N.K. Norval M. Traynor N.J. Wolf M. Johnson B.E. Crosby J. Action spectra for the trans to cis photoisomerisation of urocanic acid in vitro and in mouse skin.Photochem Photobiol. 1993; 57: 584-590Crossref PubMed Scopus (75) Google Scholar confirmed this hypothesis by producing an action spectrum for trans- to cis-UCA photoisomerization in mouse skin in vivo which peaked at 310–315 nm rather than at the trans-UCA absorption maximum of ∼270 nm. Despite the potential importance of cis-UCA as a natural immunosuppressant, the action spectrum for its production in human skin is not known.Kammeyer et al., 1995Kammeyer A. Teunissen M. Pavel S. DeRie M. Bos J. Photoisomerisation spectrum of urocanic acid in human skin and in vitro; effects of simulated solar and artificial radiation.Br J Dermatol. 1995; 132: 884-891Crossref PubMed Scopus (45) Google Scholar assessed UCA photoisomerization in three healthy subjects using filters to produce nine “narrow” (mean of ±33 nm) wavebands of UVR over the range of 295–405 nm. Three UVR doses were given at each waveband, which had been weighted for erythemal effectiveness and solar irradiance. At the higher doses used in the 305 and 326 nm bandwidths, the photostationary state was approached which makes interpretation of the resultant, weighted spectrum difficult. In order to accurately define the wavelength dependence for the formation of cis-UCA in human skin we have conducted a full action spectrum over the wavelength region of 260–340 nm in five healthy volunteers. We demonstrate how data from this action spectrum can be used to predict the ability of sunscreens to protect against UVR-induced cis-UCA formation and may assist in explaining discrepancies between sunscreens' abilities to protect against erythema and photoimmunosuppression. Figure 1 shows the percentage of cis-UCA extracted from all subjects, at each dose and waveband (260–340 nm) studied together with the mean slope (±standard error) calculated using a random effects model. These slopes were plotted against wavelength to give an action spectrum (Figure 2) which is shown together with the CIE erythemal action spectrum (CIE;McKinlay and Diffey, 1987McKinlay A.F. Diffey B.L. A reference action spectrum for ultraviolet induced erythema in human skin.CIE Res Note. 1987; 6: 17-22Google Scholar).Figure 2An action spectrum for cis-urocanic acid production in human skin in vivo. The action spectrum for cis-urocanic acid production (solid line) is plotted with vertical bars depicting the standard errors of fitted linear slopes shown in Figure 1. The cis-urocanic and spectrum is noticeably red-shifted compared to the CIE erythema action spectrum (dashed line).View Large Image Figure ViewerDownload (PPT) In this study, we present the action spectrum for the production of cis-UCA in human skin. Both the human and mouse (Gibbs et al., 1993Gibbs N.K. Norval M. Traynor N.J. Wolf M. Johnson B.E. Crosby J. Action spectra for the trans to cis photoisomerisation of urocanic acid in vitro and in mouse skin.Photochem Photobiol. 1993; 57: 584-590Crossref PubMed Scopus (75) Google Scholar) spectra peak at longer wavelengths than the absorption spectrum of trans-UCA (peak absorption at ∼270 nm). In many photochemical reactions, the absorption spectrum of the chromophore is a reliable predictor of the action spectrum for the photobiological event (e.g., chlorophyll and photosynthesis). This relationship, however, relies on the (normally valid) assumption that the quantum yield is constant across all wavebands. This assumption does not hold in the case of UCA; due to complex reactions of the the trans-UCA singlet state, the quantum yield for trans- to cis-UCA photoisomerization (Φt→c) in vitro is 0.49 at 310 nm but only 0.08 at 280 nm (Morrison et al., 1984Morrison H. Bernasconi A. Pandey G. A wavelength effect on urocanic acid e/z photoisomerisation.Photochem Photobiol. 1984; 40: 549-550Crossref PubMed Scopus (66) Google Scholar; Hanson and Simon, 1998Hanson K.M. Simon J.D. Epidermal trans-urocanic acid and the UV-A induced photoaging of the skin.Proc Natl Acad Sci USA. 1998; 95: 10576-10578Crossref PubMed Scopus (135) Google Scholar). The increased Φt→c at longer wavelengths results in a red-shifting of the action spectra peaks to wavelengths longer than the peak absorption of trans-UCA. The action spectrum can be used to examine the ability of sunscreens to protect against UVR-induced cis-UCA production.van der Molen et al., 2000van der Molen R.G. Out-Luiting C. Driller H. Claas F.H. Koerten H.K. Mommaas A.M. Broad-spectrum sunscreens offer protection against urocanic acid photoisomerization by artificial ultraviolet radiation in human skin.J Invest Dermatol. 2000; 115: 421-426Crossref PubMed Scopus (19) Google Scholar used two sunscreen preparations (T10, absorbing both UVB and UVA and B10, primarily absorbing UVB) with equal sun protection factors (SPF) against erythema of 10. The sunscreens were applied to dorsal skin and their ability to protect against broad-band UVR (Philips TL-12 Philips, Guildford, UK)-induced cis-UCA production was assessed. From the published sunscreen absorption spectra (Fig 6 invan der Molen et al., 2000van der Molen R.G. Out-Luiting C. Driller H. Claas F.H. Koerten H.K. Mommaas A.M. Broad-spectrum sunscreens offer protection against urocanic acid photoisomerization by artificial ultraviolet radiation in human skin.J Invest Dermatol. 2000; 115: 421-426Crossref PubMed Scopus (19) Google Scholar) it is possible to calculate the transmittance (T(λ)) of the two sunscreens at wavelength λ. These values are then convoluted with the relative spectral output (E(λ)) of the TL-12 source and U(λ), the efficiency of cis-UCA production from Figure 2 to predict the relative cis-UCA produced (cis) by TL-12 irradiation through each of the sunscreens. cis=∫260340E(λ)T(λ)U(λ)dλ From the above equation the protective factors against cis-UCA production for the T10 and B10 sunscreens are calculated as 4.4 and 1.9, respectively. The finding that the T10 sunscreen is more efficient at protecting against TL-12 induced cis-UCA production agrees favorably with the empirical in vivo data presented byvan der Molen et al., 2000van der Molen R.G. Out-Luiting C. Driller H. Claas F.H. Koerten H.K. Mommaas A.M. Broad-spectrum sunscreens offer protection against urocanic acid photoisomerization by artificial ultraviolet radiation in human skin.J Invest Dermatol. 2000; 115: 421-426Crossref PubMed Scopus (19) Google Scholar. These calculations emphasize that sunscreens with equal SPF will not necessarily have equal abilities to protect against cis-UCA production and perhaps suggests that they will also not protect equally against photoimmunosuppression. The implication is that the action spectra for erythema and photoimmunosuppression are different. This is supported by several studies in humans, conducted on both the sensitization and elicitation phases of CHS, demonstrating that sunscreens protecting against erythema (predominately UVB absorbers) do not show as good protection against photoimmunosuppression as broad spectrum sunscreens (UVB and UVA absorbers) (Fourtanier et al., 2000Fourtanier A. Gueniche A. Compan D. Walker S.L. Young A.R. Improved protection against solar-simulated radiation-induced immunosuppression by a sunscreen with enhanced ultraviolet A protection.J Invest Dermatol. 2000; 114: 620-627Crossref PubMed Scopus (51) Google Scholar; Baron et al., 2003Baron E.D. Fourtanier A. Compan D. Medaisko C. Cooper K.D. Stevens S.R. High ultraviolet A protection affords greater immune protection confirming that ultraviolet A contributes to photoimmunosuppression in humans.J Invest Dermatol. 2003; 121: 869-875Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar; Poon et al., 2003Poon T.S. StC Barnetson R. Halliday G.M. Prevention of immunosuppression by sunscreens in humans is unrelated to protection from erythema and dependent on protection from ultraviolet A in the face of constant ultraviolet B protection.J Invest Dermatol. 2003; 121: 184-190Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar). From Figure 2 it is clear that the cis-UCA action spectrum is red-shifted compared with the CIE erythema spectrum and this suggests that sunscreens that primarily absorb erythemogenic radiation may fail to prevent cis-UCA formation. In contrast, broad-spectrum sunscreens will be efficient at protecting against both erythema and cis-UCA formation. Whilst further studies are required to clarify the role of cis-UCA in human photoimmunosuppression, it is tempting to speculate that a failure to protect against cis-UCA production is linked to the demonstrated failure of some sunscreens to protect against immunosuppression. Five healthy Caucasian volunteers, (26–37 y), three males, skin types I–III, were enrolled in this local ethics committee approved study after giving informed consent in accordance with Declaration of Helsinki Principles. They were not taking systemic medication and had not exposed their dorsal skin to solar or artificial UVR for 3 mo prior to the study. A single grating monochromator (Rank Hilger D330 Rank Hilger, Margate, UK) with a 450 W xenon arc source was used (Gibbs et al., 1993Gibbs N.K. Norval M. Traynor N.J. Wolf M. Johnson B.E. Crosby J. Action spectra for the trans to cis photoisomerisation of urocanic acid in vitro and in mouse skin.Photochem Photobiol. 1993; 57: 584-590Crossref PubMed Scopus (75) Google Scholar). The output was directed via a 5 mm diameter liquid light guide (Oriel Corporation, Leatherhead, UK). At wavebands 330 and 340 nm a Schott WG305 cut-off filter was used. Wavelength and bandwidth (half-maximal bandwidth ∼2.6 nm) calibrations were conducted using a Bentham double-grating spectroradiometer (Bentham Instruments, Reading, UK). Irradiance was measured with a calibrated Hilger Watts 2M8 thermopile (both thermopile and spectroradiometer calibrations were traceable to the National Physical Laboratory, Teddington, UK). All irradiations were conducted in the UK winter months from November to February. Strips of double-sided adhesive tape with 9 × 5-mm diameter apertures were placed across the dorsal skin region of each subject. The skin within each aperture was irradiated using the liquid light guide with narrow wavebands centered at 260, 270, 280, 290, 300, 315, 320, 330, and 340 nm (half-maximal band width =2.6 nm). Doses were administered at 0–30 mJ per cm2 in 5 mJ per cm2 increments for wavebands 260–320 nm and 0–60 mJ per cm2 at 10 mJ per cm2 increments for wavebands 330 and 340 nm. At each waveband there were also triplicate non-irradiated sites. Immediately after irradiation, 5 mm diameter filter paper discs were inserted in each punched hole of the double-sided tape. To extract the UCA from the skin 5 μL of 0.1 M KOH were pipetted on to each disc and the area was occluded for 1 h with a polythene cover stuck on the upper adhesive side of the double side tape. The discs were subsequently placed in individual eppendorf tubes containing 195 μL of 0.1 M KOH, vortexed and stored at -20°C for up to 5 d before analysis. Standard curves of pure trans-UCA (Sigma Aldrich, Poole, UK) and chromatographically purified cis-UCA (Norval et al., 1988Norval M. McIntyre C.R. Simpson T.J. Howie S.E.M. Bardshiri E. Quantification of urocanic acid isomers in murine skin during development and after irradiation with ultraviolet B light.Photodermatology. 1988; 5: 179-186PubMed Google Scholar) were constructed at concentrations of 6.25 ng to 0.4 μg per 50 μL mobile phase buffer. HPLC was carried out as described previously (Gibbs et al., 1993Gibbs N.K. Norval M. Traynor N.J. Wolf M. Johnson B.E. Crosby J. Action spectra for the trans to cis photoisomerisation of urocanic acid in vitro and in mouse skin.Photochem Photobiol. 1993; 57: 584-590Crossref PubMed Scopus (75) Google Scholar) but using a mobile phase flow rate of 1 mL per min. Individual peaks were observed for cis- and trans-UCA, eluting after approximately 6 and 8 min, respectively. At each waveband, cis-UCA levels from each subject were quantified as a percentage of total UCA (trans+cis) extracted and plotted against UV dose. The slopes of the five subjects were calculated by regression analysis and averaged using a random effects model to allow for heterogeneity between individuals. The resultant mean slope (±standard error) was used as a measurement of the cis-UCA production rate (%cis-UCA per mJ per cm2) and plotted against wavelength to give an action spectrum. We would like to thank Dr Donald Allen for providing UVR output spectra data, Andrew Vail for statistical advice and all the subjects who took part in this study. This study was funded by a European Community collaborative grant, ENV4-CT960192." @default.
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• W2064553763 title "An Action Spectrum for the Production of cis-Urocanic Acid in Human Skin In Vivo" @default.
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