Werth V P, Zhang W, Dortzbach K, Sullivan K
The University of Pennsylvania, VA Hospital, Philadelphia, Pennsylvania, USA.
J Invest Dermatol. 2000 Oct;115(4):726-30. doi: 10.1046/j.1523-1747.2000.00118.x.
Ultraviolet irradiation stimulates keratinocytes and dermal fibroblasts to release cytokines involved in apoptosis and immunomodulation, such as tumor necrosis factor-alpha and interleukin-1alpha. Recent work has associated the -308A polymorphism of the human tumor necrosis factor-alpha promoter with systemic lupus erythematosus and adverse outcomes in several infectious diseases. To explore the role of this polymorphism in ultraviolet-induced disease, we used two approaches. First, we examined its prevalence in individuals with different ultraviolet sensitivity. Compared with healthy controls, there was a substantially increased prevalence of -308A in subacute cutaneous lupus erythematosus, an extremely photosensitive form of cutaneous lupus erythematosus, but not in discoid lupus erythematosus, a less photosensitive form. Next, to examine molecular regulation by tumor necrosis factor -308A, cultured 3T3 fibroblasts were transiently transfected with chloramphenicol acetyl transferase reporter constructs under the control of either -308A or the wild-type -308G promoter. Without added interleukin-1alpha the two constructs produced similar baseline chloramphenicol acetyl transferase activity and similar responses to ultraviolet. The responses to interleukin-1alpha, a photoinduced cytokine, were markedly different: interleukin-1alpha without ultraviolet produced a 15-fold increase in chloramphenicol acetyl transferase transcription from the -308A construct without affecting the wild-type -308G. Interleukin-1alpha plus ultraviolet B caused a remarkable 300-fold increase in -308A chloramphenicol acetyl transferase transcription over baseline, while increasing the wild type to <15% of this level. These results indicate a clear difference between the two promoters, including a striking synergy between ultraviolet B and added interleukin-1alpha in the induction of transcription by the tumor necrosis factor-alpha -308A promoter. Overall, our findings indicate a strong linkage between the -308A polymorphism and subacute systemic lupus erythematosus, which is likely to directly contribute to the photosensitivity of these patients.
紫外线照射可刺激角质形成细胞和真皮成纤维细胞释放参与细胞凋亡和免疫调节的细胞因子，如肿瘤坏死因子-α和白细胞介素-1α。最近的研究发现，人类肿瘤坏死因子-α启动子的-308A多态性与系统性红斑狼疮以及几种传染病的不良预后有关。为了探究这种多态性在紫外线诱发疾病中的作用，我们采用了两种方法。首先，我们检测了不同紫外线敏感性个体中该多态性的发生率。与健康对照相比，亚急性皮肤型红斑狼疮（一种对光极度敏感的皮肤型红斑狼疮）患者中-308A的发生率显著增加，而盘状红斑狼疮（一种对光敏感性较低的类型）患者中则未增加。接下来，为了研究肿瘤坏死因子-308A的分子调控，将氯霉素乙酰转移酶报告基因构建体在-308A或野生型-308G启动子的控制下瞬时转染培养的3T3成纤维细胞。在不添加白细胞介素-1α的情况下，两种构建体产生相似的基线氯霉素乙酰转移酶活性和对紫外线的相似反应。对光诱导细胞因子白细胞介素-1α的反应则明显不同：无紫外线时，白细胞介素-1α使-308A构建体的氯霉素乙酰转移酶转录增加15倍，而不影响野生型-308G。白细胞介素-1α加紫外线B使-308A氯霉素乙酰转移酶转录比基线显著增加300倍，而野生型仅增加至该水平的<15%。这些结果表明两种启动子之间存在明显差异，包括紫外线B与添加的白细胞介素-1α在肿瘤坏死因子-α -308A启动子诱导转录方面具有显著协同作用。总体而言，我们的研究结果表明-308A多态性与亚急性系统性红斑狼疮之间存在紧密联系，这可能直接导致这些患者的光敏感性。
