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TNF-α production in the skin

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Abstract

Upregulation of TNF-α is a key early response to ultraviolet B (UVB) by keratinocytes (KCs), and represents an important component of the inflammatory cascade in skin. UVB irradiation induces TNF-α expression in both KCs and dermal fibroblasts, with TNF-α mRNA induction seen as early as 1.5 h after UVB. We previously reported that the effects are wavelength-specific: TNF-α expression and secretion are induced by UVB (290–320 nm), but not by UVA (320–400 nm). Moreover, we found that IL-1α, a cytokine also present in irradiated skin, substantially and synergistically enhances the induction of TNF-α by UVB, and the induction of TNF-α by this combination of UVB with IL-1α is mediated through increased TNF-α gene transcription. We investigated the molecular mechanism for UVB-induction of the TNF-α gene with a series of TNF-α promoter constructs, ranging from 1.2 kbp (from −1179 to +1 with respect to the TNF-α transcription initiation site) down to 0.1 kbp (−109 to +1), each driving expression of a CAT reporter. Our results showed a persistent nine to tenfold increase of CAT activity in all TNF-α promoter/reporter constructs in response to UVB (30 mJ/cm2) exposure. These results indicate the presence of UVB-responsive cis-element(s) located between −109 and +1 of the TNF-α promoter, a region that contains a putative AP-1 site and a putative NFkB site. UVB-induction was abolished when the TNF-α promoter was mutated by one base pair at the AP-1 binding site. Cells treated with SP600125, an AP-1 inhibitor that inhibits JNK (c-Jun N-terminal kinase), also showed suppression of the 0.1 kbp TNF-α promoter/reporter construct. The authentic endogenous gene in untransfected cells was also blocked by the inhibitor. Electrophoretic Mobility Shift Assay indicated new complexes from UVB-treated nuclear extracts and anti-phospho-c-Jun, a regulatory component of the AP-1 transcription factor, creating a supershift indicating increased phosphorylation of c-Jun and hence higher AP-1 activity. Keratinocyte-derived TNF-α is a component of the early induction phase of the inflammatory cascade.

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Abbreviations

KCs:

Keratinocytes

FBs:

Fibroblasts

UVB:

Ultraviolet B

TNF-α:

Tumor necrosis factor-α

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Acknowledgment

The work is supported by a V.A. Merit Review Grant (V.P.W).

Conflict of interest statement

The authors have no potential conflict of interest.

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Authors and Affiliations

  1. Department of Dermatology, University of Pennsylvania, 2, Rhodes Pavilion, 3600 Spruce Street, Philadelphia, PA, 19104, USA

    M. M. Bashir, M. R. Sharma & V. P. Werth

  2. Medical Research, Philadelphia VAMC, Philadelphia, PA, USA

    V. P. Werth

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  1. M. M. Bashir
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Correspondence to V. P. Werth.

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Bashir, M.M., Sharma, M.R. & Werth, V.P. TNF-α production in the skin. Arch Dermatol Res 301, 87–91 (2009). https://doi.org/10.1007/s00403-008-0893-7

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