UROCANIC ACID, SUNLIGHT & IMMUNITY--A NOVEL INTERACTION

尿刊酸、阳光

• 批准号: 2095500
• 负责人: EDWARD C DEFABO
• 金额: $ 28.03万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-12-04 至 1998-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2095500
• 关键词: antigen presentation; antigen presenting cell; autoradiography; cis trans isomerization; cytokine; dietary aminoacid; gene induction /repression; histidine; laboratory mouse; nonvisual photoreceptor; nutrition related neoplasm /cancer; nutrition related tag; radiation carcinogenesis; radiation dosage; radiation immunosuppression; receptor binding; skin neoplasms; solar radiation; ultraviolet radiation; urocanate

Ultraviolet B radiation (UVB) contains the shortest wavelengths of sunlight penetrating to the Earth's surface (290-320nm). These wavelengths are directly linked to skin cancer formation and immunological alterations leading to systemic immunosuppression in mammals. Experimental studies strongly link this suppression to skin cancer. Irradiation of the skin with UVB is systemically suppressive of contact hypersensitivity reactions (CHS) to chemicals, delayed type hypersensitivity responses (DTH) to hapten-conjugated cells, to viruses, and to parasites. UV irradiation also suppresses the DTH response to alloantigens, and has been shown to prolong experimental allograft acceptance. UV suppression prevents the immunologic rejection of highly antigenic UV tumors. We proposed that immune suppression of T-cell immunity is protective and evolved to prevent autoimmune attack against skin cells containing sunlight-induced "photoantigens". UV suppression provides time to synthesize new skin without the "photoantigens". This hypothesis predicts that too much sun exposure could lead to inadvertent protection of any pre-existing skin tumor cells as well. Our research has been aimed at understanding the mechanism by which UV radiation induces immunosuppression. Our most critical finding was that suppression of CHS was mediated by the presence, on the outermost layer of skin, of an unusual photoreceptor capable of initiating immune suppression. We identified this photoreceptor as urocanic acid (UCA), de-aminated histidine. In this proposal we expand our studies to include (i) the effects of UV radiation on cytokine induction and localization; cytokines are important immunoregulatory signals recently shown to be activated by UVB irradiation of skin; (2) studies to isolate and identify the cell receptor for cis UCA binding; experimental evidence indicates this to be the moiety which initiates immune suppression and to study the mechanism of antigen-presenting cell alteration by UV and cis UCA; (3) the effects of UVA radiation on UVB- induced immune suppression since UVA may modulate the expression of UVB- induced suppressor signals through the UVA-UVB ratio which changes throughout sunlight exposure; and (4) the effects of the amino acid L- histidine on skin cancer because of its ability to enhance immune suppression through cis UCA formation. Significance:UV-induced immune suppression has now been confirmed in humans and appears to be independent of pigmentation. In addition to skin cancer growth, the development of certain types of cell-mediated infectious diseases appear to be influenced by UV suppression. Recently published laboratory experiments indicate a potential role for UV-B,cis UCA in delaying the rejection of transplanted tissue. This opens up the possibility of using UCA as a therapeutic agent in delaying the rejection of transplanted organs and tissues. Finally, significant stratospheric ozone reduction has become a reality over populated areas of the Northern Hemisphere. We recently showed that the doses of UVB used experimentally to induce suppression can be achieved by natural sunlight exposure over most populated countries between 40 N and 40 S in summertime. Immune suppressing solar UVB irradiances may, therefore, be expected to increase by stratospheric ozone depletion over large populated areas of the world. Given the significant losses of ozone over the U.S. during summer 1993 (10-20%) this may have already occurred.

紫外线B辐射(UVB)包含最短波长的 穿透地球表面的阳光(290-320纳米)。这些波长 与皮肤癌的形成和免疫改变直接相关 导致哺乳动物的全身性免疫抑制。实验研究 这种抑制与皮肤癌密切相关。皮肤的照射 UVB对接触性过敏反应有系统抑制作用 (CHS)对化学品、迟发型超敏反应(DTH) 半抗原结合的细胞，对病毒和寄生虫。紫外线照射也 抑制DTH对同种异体抗原的反应，并已被证明延长 实验性同种异体移植接受率。紫外线抑制可预防免疫学 高抗原性紫外线肿瘤的排斥反应。我们提出了免疫 抑制T细胞免疫是保护性的，并进化为防止 对含有阳光的皮肤细胞的自身免疫攻击 “光抗原”。紫外线抑制为合成新皮肤提供了时间 没有“光抗原”。这一假说预言，阳光过多 暴露可能会导致对任何先前存在的皮肤的无意保护 肿瘤细胞也是如此。我们的研究旨在了解 紫外线辐射诱导免疫抑制的机制。我们最大的 关键的发现是CHS的抑制是由存在介导的， 在皮肤的最外层，一种不寻常的光感受器能够 启动免疫抑制。我们确认这个感光器是 尿毒酸(UCA)，去氨基组氨酸。在这项建议中，我们将扩大我们的 研究包括：(一)紫外线辐射对细胞因子诱导的影响 和定位；细胞因子是重要的免疫调节信号 最近被证明是通过紫外线照射皮肤而激活的；(2)研究 分离和鉴定顺式UCA结合的细胞受体；实验 有证据表明，这是启动免疫的部分 抗原提呈细胞的抑制及其机制的研究 紫外线和顺式UCA的变化；(3)UVA辐射对UVB- 诱导免疫抑制，因为UVA可能调节UVB-1的表达 通过UVA/UVB比值的变化诱导抑制信号 以及(4)氨基酸L的影响-- 组氨酸对皮肤癌的治疗作用，因为它能增强免疫力 通过顺式UCA地层进行压制。意义：紫外线诱导免疫 抑制现已在人类中得到证实，而且似乎是独立的 色素沉着。除了皮肤癌的生长外， 某些类型的细胞介导的传染病似乎受到了影响。 通过紫外线抑制。最近公布的实验室实验表明， UV-B、顺式UCA在延缓移植排斥反应中的潜在作用 组织。这开启了使用UCA作为治疗剂的可能性。 延缓移植器官和组织的排斥反应。最后， 平流层臭氧的显著减少已经成为现实 北半球人口稠密的地区。我们最近展示了 实验中用于诱导抑制的UVB剂量可以通过以下方式实现 大多数人口稠密国家的自然日照曝光量在40 N到40 N之间 40 S在夏天。免疫抑制太阳UVB辐射可能， 因此，预计平流层臭氧消耗将增加超过 世界上人口众多的地区。考虑到臭氧的大量损失 在1993年夏季的美国，这种情况可能已经发生了(10%-20%)。