Association of a promoter polymorphism of tumor necrosis factor-alpha with subacute cutaneous lupus erythematosus and distinct photoregulation of transcription.
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.
Werth
V P
VP
The University of Pennsylvania, VA Hospital, Philadelphia, Pennsylvania, USA. werth@mail.med.upenn.edu
Zhang
W
W
Dortzbach
K
K
Sullivan
K
K
D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D015331:Cohort Studies; D017930:Genes, Reporter / Q000502:physiology; D006801:Humans; D008178:Lupus Erythematosus, Cutaneous / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D014158:Transcription, Genetic / Q000528:radiation effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D014466:Ultraviolet Rays
D014409:Tumor Necrosis Factor-alpha; D015500:Chloramphenicol O-Acetyltransferase