The role of urocanic acid in UVB-induced suppression of immunity to Trichinella spiralis infection in the rat.
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The naturally occurring trans-isomer of urocanic acid (trans-UCA), found in the stratum corneum, absorbs ultraviolet light (UV) and isomerizes to the cis-form. Cis-UCA has been shown to impair some cellular immune responses, and has been proposed as an initiator of the suppression that follows UV irradiation. UVB exposure leads to an increase in cis-UCA in the skin of rats from about 10% to 40% of the total UCA. Previously it has been demonstrated that UVB lowers immune responses to Trichinella spiralis after oral infection of rats with the parasitic worm. In the present study we investigated the role of cis-UCA in the control of this parasitic infection. Rats were infected orally with T. spiralis and injected with different doses of cis- or trans-UCA subcutaneously. Mitogenic responses and the mixed lymphocyte reaction were not affected by either isomer. In contrast, the number of T. spiralis larvae in muscle tissue of infected rats was increased significantly in the cis-UCA-treated animals compared with the trans-UCA-treated animals. In addition, delayed-type hypersensitivity (DTH) to T. antigen in infected rats was significantly impaired by cis-UCA but not by trans-UCA. If rats were injected with a monoclonal antibody with specificity for cis-UCA 2 hr prior to UVB exposure, the UVB-induced suppression in DTH to T. spiralis and the increase in larvae counts were significantly inhibited compared with rats that were similarly injected with a control antibody. Thus cis-UCA can inhibit the specific resistance to parasitic infections and acts as an important mediator of UVB-induced suppression of immunity to T. spiralis in the rat. (+info)
The UV waveband dependencies in mice differ for the suppression of contact hypersensitivity, delayed-type hypersensitivity and cis-urocanic acid formation.
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Solar radiation contains ultraviolet B (280-315 nm) and ultraviolet A (ultraviolet AII, 315-340 nm; ultraviolet AI, 340-400 nm) wavebands. Ultraviolet B is known to suppress certain aspects of cell mediated immunity. Using three ultraviolet lamps (the broad-band ultraviolet B TL-12, the narrow-band ultraviolet B TL-01 and an ultraviolet AI source), we investigated the dose and waveband dependencies for the suppression of contact hypersensitivity to oxazolone and delayed-type hypersensitivity to herpes simplex virus, plus the formation of cis-urocanic acid in C3H/HeN mice. A single exposure of 1500 J/m2 TL-12 or 10,000 J/m2 TL-01 or 500,000 J/m2 ultraviolet AI corresponded to 1 minimum erythema dose in this mouse strain. The percentage of cis-urocanic acid of the total urocanic acid rose from a background level of 1.7% to 40% with 1000 J/m2 TL-12 or 10,000 J/m2 TL-01, but only 17% cis-urocanic acid was obtained with 500,000 J/m2 ultraviolet AI. The contact hypersensitivity response was significantly suppressed after a minimum dose of 5000 J/m2 TL-12 or 50,000 J/m2 TL-01 or 500,000 J/m2 ultraviolet AI. The delayed-type hypersensitivity response was suppressed by a minimum dose of 100 J/m2 TL-12 or 10,000 J/m2 TL-01 or 1000 J/m2 ultraviolet AI. So, whereas a low dose of ultraviolet AI reduced the delayed-type hypersensitivity response, a 500-fold higher dose was required to suppress contact hypersensitivity. There was no correlation between the suppression of these responses and the concentration of cis-urocanic acid in the skin. Thus different mediators may modulate the various immune responses affected by ultraviolet exposure, depending on the wavelength of the radiation. (+info)
Urocanic acid isomers are good hydroxyl radical scavengers: a comparative study with structural analogues and with uric acid.
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UV-exposure of the epidermis leads to the isomerisation of trans-UCA into cis-UCA as well as to the generation of hydroxyl radicals. This study shows by means of the deoxyribose degradation test that UCA isomers are more powerful hydroxyl radical scavengers than the other 4-(5-)substituted imidazole derivatives, such as histidine, though less powerful than uric acid. UCA, present in relatively high concentrations in the epidermis, may well be a major natural hydroxyl radical scavenger. (+info)
Interferon-gamma is involved in photoimmunoprotection by UVA (320-400 nm) radiation in mice.
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Ultraviolet B radiation not only inflicts tumor-initiating DNA damage, but also impairs T cell-mediated immunity relevant to survival of the initiated cells. We have reported, however, that ultraviolet A radiation, in contrast, is immunologically innocuous in hairless mice and opossums, but renders the animals resistant to the immunosuppression by ultraviolet B, or its mediator cis-urocanic acid. Ultraviolet B irradiation of skin causes abundant release of numerous cytokines (interleukin-1, interleukin-6, interleukin-10, tumor necrosis factor-alpha); notably interleukin-12 and interferon-gamma do not appear to be upregulated. A recent report has indicated that interleukin-12 protects from photoimmunosuppression in mice, but it remains unclear whether interleukin-12 acts directly or via interferon-gamma, which it is known to stimulate. Here we investigate the possible role of interferon-gamma in UVA photoimmunoprotection, using interferon-gamma gene knockout mice in comparison with control C57/BL6 mice, and the systemic contact hypersensitivity reaction (induced by sensitization through a nonirradiated skin site) to measure immunity. interferon-gamma-/- mice raised normal contact hypersensitivity responses, and were unaffected, as were C57BL control mice, by ultraviolet A exposure. In response to ultraviolet B irradiation or topical cis-urocanic acid treatment, control mice became immunosuppressed by 69% and 27%, respectively, and interferon-gamma-/- mice by 79% and 27%. When ultraviolet B exposure or cis-urocanic acid was followed by ultraviolet A irradiation, however, contact hypersensitivity was totally restored in control mice, but remained suppressed by 55% and 25%, respectively, in interferon-gamma-/- mice. Injection of recombinant interferon-gamma in the interferon-gamma-/- mice restored the ultraviolet A protective effect against cis-urocanic acid-induced immunosuppression. These observations suggest that interferon-gamma plays a part in ultraviolet A immunoprotection from the suppressive effect of ultraviolet B radiation and, and that the mechanism appears to be via antagonism by this cytokine of the cis-urocanic acid immunosuppressive action. (+info)
Heme oxygenase induction mediates the photoimmunoprotective activity of UVA radiation in the mouse.
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In contrast to the immunosuppressive potential of UVB (280-320 nm) radiation in experimental animals and humans, UVA (320-400 nm) radiation at environmentally relevant doses appears to be immunologically inert. However, such exposure to UVA radiation has been observed unexpectedly to induce resistance to UVB-induced immunosuppression in mice, by a mechanism resulting in the inactivation of cis-urocanic acid (UCA), an epidermal immunosuppressive UV photoproduct. In this study in mice, we show that the immunoprotective activity of UVA radiation, against the effects of both UVB radiation and cis-UCA, can be attributed to the induction of cutaneous heme oxygenase (HO; EC 1.14.99.3). Cell-mediated immune function was assessed in vivo by the contact hypersensitivity response induced to oxazolone at an unirradiated skin site, and HO enzyme activity was measured in cutaneous microsomal preparations from treated mice. There was a progressive increase in HO enzyme activity for at least 3 days after UVA irradiation. However HO activity, both constitutive and UVA radiation-induced, was sensitive to the effects of injecting mice with the specific HO inhibitor, tin protoporphyrin (Sn [IV] protoporphyrin IX; SnPP). We observed, in addition, that in SnPP-injected mice, the immunoprotective effect of UVA radiation against either UVB radiation or cis-UCA was abrogated. Because SnPP injection did not affect normal contact hypersensitivity responsiveness but did inhibit the constitutive HO enzyme activity, it appeared that only the inducible HO was active in modulating immune function. This finding indicates that UVA-induced HO activity is a major player in the skin defenses against UVB immunosuppression. (+info)
Lack of metallothionein-I and -II exacerbates the immunosuppressive effect of ultraviolet B radiation and cis-urocanic acid in mice.
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The effect of a null mutation for the metallothionein (MT)-I and -II isoforms in mice on the immunosuppressive action of ultraviolet B (UVB; 280-320 nm) radiation has been examined. Mice were exposed to a series of increasing daily UVB doses, each dose administered to the dorsum on 3 consecutive days. Erythema was assessed, and measured as its oedema component by the post-irradiation dorsal skinfold thickness, but there was no effect of the null mutation (MT-/-) observed after 3 x 3.4 kJ/m2 of UVB radiation. Immune function was assessed by the contact hypersensitivity (CHS) response, which was initiated by sensitization on unirradiated abdominal skin, and thus demonstrated the systemic effects of dorsal treatments. In comparison with the wild-type MT+/+ mouse, the MT-/- mouse was significantly more immunosuppressed by moderate daily UVB doses (1. 75-5.9 kJ/m2). When topically applied cis-urocanic acid (cis-UCA) replaced UVB radiation as the immunosuppressive agent, contact hypersensitivity in MT-/- mice was again markedly more suppressed than in MT+/+ mice, in a dose-responsive manner. The results infer that MT, which was shown immunohistochemically to be strongly induced in the epidermis of MT+/+ mice, but to be absent in MT-/- epidermis, has the potential to protect from photoimmunosuppression, and that the mechanism of action may be via the inactivation of the epidermal UVB-photoproduct, cis-UCA. (+info)
Evidence for the existence of a self-regulated enzymatic process within the human stratum corneum -an unexpected role for urocanic acid.
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The existence of a flux of proton donors from skin (inner part of the forearm) to the electrode was observed in 12 male and female volunteers. This flux was used to collect and identify the ionic species responsible for skin acidity. It was then found that: (i) pK of these proton donors (pK = 6.13 +/- 0.07) was quasi-identical to that of trans-urocanic acid (6.10), and (ii) the amount of urocanic acid present in stratum corneum was sufficient in itself to explain the acidic level as measured with pH meter (R = 0.8484, n = 10, p = 0.00136). As a result, the contribution of other ionic species can be considered as negligible in normal human skin. The data recorded led us to identify three groups (Fast, Medium, and Slow) characterized by different skin surface pH values (low, medium, and close to neutral) and showing a pH gradient in the outer layers of the stratum corneum, or not. Data analysis suggests that these characteristics depend on urocanic acid production rate within the stratum corneum and that this production rate is self-regulated by its urocanic acid content. (+info)
Broad-spectrum sunscreens offer protection against urocanic acid photoisomerization by artificial ultraviolet radiation in human skin.
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Cis-urocanic acid (UCA) has been indicated as an important mediator of ultraviolet (UV)-induced immunosuppression. In this study we describe a rapid, noninvasive method for the determination of the protective capacity of various sunscreens against the UV-induced isomerization of trans-UCA into its cis form. For this purpose we applied sunscreens prior to in vivo exposure of human volunteers with single or repeated broadband UVB irradiations of 100 mJ per cm2. We found significant but different levels of protection against UCA photoisomerization by all sunscreens that correlated with the sun protection factor. A comparison of various sunscreens with a sun protection factor of 10, showed that the best protection was offered by the sunscreens (containing organic UV filters or TiO2) with broad absorption spectra. The ability to inhibit cis-UCA formation was not influenced by the penetration characteristics of sunscreens, as determined by application of the sunscreen on quartz glass that was placed on the skin, preventing penetration of sunscreen in the skin. In addition ex vivo UV exposure of human skin was employed to permit other tests of immunomodulation, in this case the mixed epidermal cell lymphocyte reaction. The advantage of this ex vivo method is that there is no need to take biopsies from volunteers. Ex vivo irradiation of human skin with a single dose of 200 mJ per cm2 resulted in similar protection by the sunscreens against cis-UCA formation as in the in vivo system. Furthermore, the mixed epidermal cell lymphocyte reaction data correlated with the cis-UCA findings. We conclude that UCA isomerization is an excellent method to determine sunscreen efficacy and that broad-spectrum sunscreens offer good immunoprotection. (+info)