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1.
J Immunol ; 167(11): 6232-8, 2001 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-11714785

RESUMEN

UV radiation induces skin cancer primarily by its DNA-damaging properties, but also by its capacity to suppress the immune system. The photoisomer of urocanic acid (UCA), cis-UCA, is an important mediator of UV-induced immunosuppression and is involved in the inhibition of tumor immunity. The immunomodulatory cytokine IL-12 is known to counteract many of the immunosuppressive effects of UV radiation, including UV-induced immune tolerance. In this study, we addressed whether IL-12 also reverts the immunosuppressive activities of cis-UCA. Cis-UCA inhibits the ability of Langerhans cells to present tumor Ags for primary and secondary tumor immune responses. IL-12 treatment completely prevented the suppression by cis-UCA. IL-12 also protected mice from cis-UCA-induced suppression of contact hypersensitivity responses. To study the effects of cis-UCA on Ag-processing and Ag-presenting function in vitro, Langerhans cells were treated with UCA isomers and incubated with OVA or OVA peptide(323-339) before exposure to OVA-specific transgenic T cells. Cis-, but not trans-UCA suppressed Ag presentation, which was completely reversed upon addition of IL-12. Since these findings suggest that cis-UCA may play an important role in photocarcinogenesis by inhibiting a tumor immune response, mice were chronically UVB irradiated to induce skin cancer. Whereas all mice in the control groups developed tumors, mice treated with a mAb with specificity for cis-UCA showed a significantly reduced tumor incidence. These data strongly indicate the importance of cis-UCA during photocarcinogenesis and support the concept of counteracting cis-UCA as an alternative strategy to prevent UV-induced skin cancer, possibly via the application of IL-12.


Asunto(s)
Presentación de Antígeno/inmunología , Antígenos de Neoplasias/metabolismo , Inmunosupresores/antagonistas & inhibidores , Interleucina-12/fisiología , Células de Langerhans/inmunología , Neoplasias Inducidas por Radiación/inmunología , Rayos Ultravioleta , Ácido Urocánico/antagonistas & inhibidores , Animales , Presentación de Antígeno/efectos de los fármacos , Antígenos de Neoplasias/inmunología , Dermatitis por Contacto/inmunología , Dermatitis por Contacto/prevención & control , Epítopos de Linfocito T/inmunología , Femenino , Sueros Inmunes/administración & dosificación , Inmunización Pasiva , Inmunosupresores/farmacología , Inyecciones Intraperitoneales , Células de Langerhans/efectos de los fármacos , Células de Langerhans/metabolismo , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos A , Ratones Endogámicos BALB C , Ratones Transgénicos , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/prevención & control , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Células Tumorales Cultivadas , Ácido Urocánico/administración & dosificación , Ácido Urocánico/inmunología , Ácido Urocánico/farmacología
2.
Photochem Photobiol ; 74(6): 765-70, 2001 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11783931

RESUMEN

Studies of the photoimmunoprotective properties of sunscreens have produced disparate results. In this study in hairless mice, we compared two UVB absorbers, 2-ethylhexyl-p-methoxycinnamate (2-EHMC) and octyl-N-dimethyl-p-aminobenzoate (o-PABA), individually formulated in a common base lotion with a sunburn protection factor of 6. We measured their capacity to protect against suppression of the contact hypersensitivity (CHS) induced by three daily exposures of the dorsum to 6x the minimal erythemal/edematous dose (MED) of solar-simulated UV radiation (SSUV), in comparison with base lotion-treated mice exposed to 3 x 1 MED of SSUV. All treatments produced a similar minimal erythema. CHS was equally suppressed in mice irradiated through o-PABA and base lotion, but the suppression was significantly reduced in mice irradiated through 2-EHMC. Neither UVB absorber inhibited the epidermal photoisomerization to the immunosuppressive mediator, cis-urocanic acid. However, when mice were treated with exogenous cis-urocanic acid topically on the dorsum, but not when injected subcutaneously on the abdomen, suppression of CHS was observed in o-PABA- and base lotion-treated mice, but not in 2-EHMC-treated mice. Thus, the enhanced immunoprotection in mice irradiated through 2-EHMC apparently resulted from the direct inactivation of epidermal cis-urocanic acid by 2-EHMC. We conclude that comparative assessment of photoimmunoprotection by UV absorbers requires SSUV, erythemally matched exposures and consideration of potential interactions with cutaneous molecules.


Asunto(s)
Piel/efectos de los fármacos , Piel/efectos de la radiación , Protectores Solares/farmacología , Rayos Ultravioleta/efectos adversos , Ácido 4-Aminobenzoico/farmacología , Animales , Cinamatos/farmacología , Dermatitis por Contacto/etiología , Dermatitis por Contacto/inmunología , Edema/prevención & control , Eritema/prevención & control , Femenino , Ratones , Ratones Pelados , Fotobiología , Piel/inmunología , Estereoisomerismo , Ácido Urocánico/antagonistas & inhibidores , Ácido Urocánico/química , Ácido Urocánico/efectos de la radiación , para-Aminobenzoatos
3.
J Immunol ; 157(7): 2891-9, 1996 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-8816394

RESUMEN

Urocanic acid (UCA) occurs naturally in the stratum corneum of the skin as the trans-isomer and, upon exposure to UVB radiation, converts to cis-UCA. It has been proposed that trans-UCA is the photoreceptor for and, following its isomerization to cis-UCA, a mediator of the suppressive effects of UVB irradiation on systemic T cell-mediated immune responses, such as contact hypersensitivity (CH) and delayed-type hypersensitivity (DTH). To address this question directly, we studied the consequence of deleting the in vivo function of cis-UCA on systemic suppression of CH and DTH, by injecting mice with a anti-cis-UCA mAb several hours before exposure to UVB radiation. We found that while DTH responses were completely restored, the anti-cis-UCA Ab had no effect on UV-induced immunosuppression of the CH response, even though suppressor cell formation was inhibited in both cases. Further, the kinetics of IL-10 expression in the skin of irradiated mice injected with the anti-cis-UCA mAb was altered and the diminished APC function of spleen-adherent cells from UVB-irradiated mice was totally reversed by the Ab. These findings suggest that cis-UCA acts as a mediator for some but not all of the systemic suppressive effects of UVB irradiation. They also suggest that cis-UCA may act indirectly via IL-10 to modulate immune function.


Asunto(s)
Anticuerpos Monoclonales/inmunología , Células Presentadoras de Antígenos/inmunología , Dermatitis Alérgica por Contacto/inmunología , Hipersensibilidad Tardía/inmunología , Terapia de Inmunosupresión , Transducción de Señal/efectos de la radiación , Piel/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Rayos Ultravioleta , Ácido Urocánico/antagonistas & inhibidores , Traslado Adoptivo , Animales , Eritrocitos/inmunología , Interleucina-10/fisiología , Isomerismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Oxazolona/inmunología , Ovinos/sangre , Piel/metabolismo , Piel/efectos de la radiación , Organismos Libres de Patógenos Específicos , Bazo/inmunología , Ácido Urocánico/química , Ácido Urocánico/inmunología , Ácido Urocánico/efectos de la radiación
4.
Photochem Photobiol ; 63(3): 322-7, 1996 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-8881338

RESUMEN

A recent study has shown that N-acetylcysteine (NAC) not only has sun-protective properties but also inhibits the UVB-induced suppression of contact hypersensitivity (CHS) in mice. Because NAC does not absorb any UVA (320-400 nm radiation) or UVB (290-320 nm radiation) we have studied the underlying mechanism of protection. Irradiation of solutions of plasmid DNA with UVC (200-290 nm radiation) (10 J m-2) resulted in the formation of cyclobutane pyrimidine dimers, but the extent to which this occurred was not affected by the presence of NAC as was determined by an in vitro T4 endonuclease assay. N-acetylcysteine proved not to have any effect on the photoisomerization of trans-urocanic acid (UCA) to its cis-form in vitro; at equilibrium, approximately 55% cis-UCA was formed. The same percentage was also found in vivo on exposure of mice to UVB (15 kJ m-2). Topical application of NAC 30 min prior to irradiation did not have any influence as well on the photoisomerization of trans- to cis-UCA. These in vivo experiments were performed under the same conditions used previously to show the protective effect of NAC against UVB-induced suppression of CHS. We conclude that this protection of NAC is at least partly based on interference in the role of cis-UCA in UVB-induced suppression of CHS. This conclusion is supported by the observation that NAC completely inhibits the suppression of CHS by cis-UCA administered to mice that were always kept in the dark. In the same range of doses as used in the present study, it was shown in our previous study that NAC alone does not affect the CHS response.


Asunto(s)
Acetilcisteína/farmacología , Tolerancia Inmunológica/efectos de los fármacos , Tolerancia Inmunológica/efectos de la radiación , Protectores Solares/farmacología , Rayos Ultravioleta/efectos adversos , Ácido Urocánico/antagonistas & inhibidores , Animales , Dermatitis por Contacto/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ácido Urocánico/farmacología
5.
Am J Clin Nutr ; 61(3): 571-6, 1995 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-7872221

RESUMEN

Evidence exists implicating the epidermal ultraviolet B (UVB) photoproduct cis-urocanic acid as an immunogenic mediator of the systemic suppression of T cell-mediated immunity by UVB exposure. Cis-urocanic acid appears to act via histamine receptor pathways, and histamine receptor antagonists and other imidazole ring compounds may modify its immune suppressing action. A component of the food coloring substance ammonia caramel, 2-acetyl-4-tetrahydroxybutylimidazole (THI), which is known to cause lymphopenia in rats, appears to suppress immunity by a similar pathway when the contact hypersensitivity reaction has been the immune function assay in mice. The induction of lymphopenia in rats by THI is inhibited by the vitamin pyridoxine. This study demonstrates that the suppression of contact hypersensitivity in mice by UVB radiation, cis-urocanic acid, or THI is strongly inhibited by supplemental pyridoxine, fed at 30 mg/kg diet, in comparison with the normal diet, which supplies 7 mg pyridoxine/kg diet. These results suggest that pyridoxine competes with cis-urocanic acid and THI for the same binding site or receptor, which we postulate to be a histamine-like T lymphocyte receptor, and that a role may exist for the control of photoimmunosuppression by this vitamin.


Asunto(s)
Dermatitis por Contacto/prevención & control , Imidazoles/toxicidad , Inmunosupresores/toxicidad , Piridoxina/uso terapéutico , Rayos Ultravioleta/efectos adversos , Ácido Urocánico/toxicidad , Animales , Dermatitis por Contacto/etiología , Dermatitis por Contacto/inmunología , Dieta , Imidazoles/antagonistas & inhibidores , Inmunosupresores/antagonistas & inhibidores , Ratones , Ácido Urocánico/antagonistas & inhibidores
6.
Immunology ; 78(1): 99-104, 1993 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-8436408

RESUMEN

Carnosine is a naturally occurring histidine-containing dipeptide in mammalian tissues for which a physiological role has not been defined. It has antioxidant properties, but has also been shown to be related metabolically to histidine and histamine, and to have immunopotentiating properties in vivo. It is shown here that carnosine presented topically or in the diet, potentiated the contact hypersensitivity reaction in hairless mice. Carnosine also prevented the systemic suppression of this reaction following exposure of the dorsal skin to ultraviolet B (UVB) radiation. Furthermore, carnosine prevented the systemic suppression caused by a topically applied lotion containing cis urocanic acid, indicating that it may act in competition with this UVB photoproduct which is believed to initiate many of the suppressive effects of UVB radiation.


Asunto(s)
Carnosina/farmacología , Dermatitis por Contacto/inmunología , Tolerancia Inmunológica/efectos de los fármacos , Ácido Urocánico/antagonistas & inhibidores , Administración Cutánea , Animales , Carnosina/administración & dosificación , Dieta , Femenino , Tolerancia Inmunológica/efectos de la radiación , Ratones , Ratones Pelados , Rayos Ultravioleta , Ácido Urocánico/farmacología
7.
Clin Exp Immunol ; 72(1): 174-7, 1988 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-3396218

RESUMEN

Cis-urocanic acid (cis-UCA), produced from trans-UCA (a normal component of epidermis) by UV irradiation, suppressed cell-mediated immunological reactions in vivo and in vitro. It suppressed the development of contact hypersensitivity (CHS) when injected into mice, and it suppressed leucocyte adherence inhibition (LAI) reactions of previously sensitized lymphocytes exposed to antigen. Serum from mice injected with cis-UCA was also immunosuppressive in vitro. Normal murine spleen cells cultured with cis-UCA produced a non-dialysable factor which suppressed LAI reactivity. Trans-UCA was ineffectual in all of these systems. Both the ability of cis-UCA to induce an immunosuppressive serum factor and its ability to suppress CHS were abrogated by prior administration of cyclophosphamide, indicating that cis-UCA (normally from irradiated epidermis) stimulates T suppressor cells to produce the previously described suppressor factor in serum and the immunosuppression associated with short-term irradiation.


Asunto(s)
Dermatitis por Contacto/inmunología , Imidazoles/farmacología , Tolerancia Inmunológica/efectos de la radiación , Rayos Ultravioleta , Ácido Urocánico/farmacología , Animales , Ciclofosfamida/farmacología , Tolerancia Inmunológica/efectos de los fármacos , Prueba de Inhibición de Adhesión Leucocitaria , Ratones , Ácido Urocánico/antagonistas & inhibidores
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