IL-12 completely blocks ultraviolet-induced secretion of tumor necrosis factor alpha from cultured skin fibroblasts and keratinocytes.
IL-12 completely blocks ultraviolet-induced secretion of tumor necrosis factor alpha from cultured skin fibroblasts and keratinocytes.
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IL-12 完全阻断紫外线诱导的培养皮肤成纤维细胞和角质细胞分泌肿瘤坏死因子 α。
DOI：
10.1046/j.1523-1747.2003.12012.x
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发表时间：
2003
期刊：
影响因子：
--
通讯作者：
Zhang,Wei
中科院分区：
文献类型：
--
作者：
Werth,VictoriaP;Bashir,MuhammadM;Zhang,Wei
白细胞介素-12是其他细胞因子的重要调节因子。虽然白细胞介素-12被认为主要作用于淋巴细胞，引发从辅助性T 2细胞向辅助性T 1细胞的转变和淋巴细胞源性肿瘤坏死因子α的增加，但我们假设白细胞介素-12也可能影响皮肤细胞的肿瘤坏死因子α分泌。在这项研究中，角质形成细胞用紫外线b、紫外线a或假照射处理，不含或有外源性白细胞介素-12。值得注意的是，外源性白细胞介素-12完全阻断了紫外线b诱导的肿瘤坏死因子α的产生。紫外线a和紫外线b均能诱导白细胞介素-12的产生。为了确定这种作用的分子机制，我们在野生型（-308G）人肿瘤坏死因子α启动子的1.2 kb片段控制下，使用氯霉素乙酰转移酶报告基因，发现白细胞介素-12显著抑制启动子活性。使用人类肿瘤坏死因子α启动子-308A变体的研究显示，总体上启动子活性要高得多，但对白细胞介素-12的抑制也更敏感。其机制不涉及白细胞介素-1受体的阻断，因为白细胞介素-12不抑制白细胞介素-1介导的胶原酶mRNA的诱导。为了确定内源性白细胞介素-12的作用，我们发现抗白细胞介素-12抗体增强了紫外线b诱导的肿瘤坏死因子α的分泌。因此，白细胞介素-12强烈抑制非炎性皮肤细胞产生肿瘤坏死因子α，主要或完全通过抑制肿瘤坏死因子α启动子前1.2 kb内的一个元件的基因转录。结果是肿瘤坏死因子α的产生从非炎症细胞转移到T辅助1细胞。由于肿瘤坏死因子α是几种光敏性皮肤病和某些形式的免疫抑制的发病机制的核心，白细胞介素-12可能具有重要的生理、病理生理和治疗作用。
Interleukin-12 is an important regulator of other cytokines. Although interleukin-12 is considered to act primarily on lymphocytes, provoking a shift from T helper 2 to T helper 1 cells and an increase in lymphocyte-derived tumor necrosis factor α, we hypothesized that interleukin-12 might also affect tumor necrosis factor α secretion from skin cells. In this study, keratinocytes were treated with ultraviolet-B, ultraviolet-A, or sham irradiation, without or with exogenous interleukin-12. Remarkably, the exogenous interleukin-12 totally blocked ultraviolet-B-induced tumor necrosis factor α production. Both ultraviolet-A and ultraviolet-B were capable of inducing interleukin-12 production. To determine the molecular mechanism of this effect, we used a chloramphenicol acetyl transferase reporter under the control of a 1.2 kb fragment of the wild-type (–308G) human tumor necrosis factor α promoter and found significant suppression of promoter activity with interleukin-12. Studies using the –308A variant of the human tumor necrosis factor α promoter showed much higher promoter activity overall, but also a greater sensitivity to suppression by interleukin-12. The mechanism did not involve blockage of the interleukin-1 receptor, because interleukin-12 did not suppress interleukin-1-mediated induction of collagenase mRNA. To determine the role of endogenous interleukin-12, we found that anti-interleukin-12 antibodies enhanced ultraviolet-B-induced tumor necrosis factor α secretion. Thus, interleukin-12 strongly inhibits tumor necrosis factorαproduction by noninflammatory skin cells, mostly or entirely through inhibition of gene transcription via an element within the first 1.2 kb of the tumor necrosis factor α promoter. The result is a shift in tumor necrosis factor α production from noninflammatory cells to T helper 1 cells. Because tumor necrosis factor α is central to the pathogenesis of several photosensitive skin diseases and certain forms of immune suppression, interleukin-12 may have important physiologic, pathophysiologic, and therapeutic roles.