Archives of Dermatological Research

, Volume 301, Issue 1, pp 87–91

TNF-α production in the skin

Review

DOI: 10.1007/s00403-008-0893-7

Cite this article as:
Bashir, M.M., Sharma, M.R. & Werth, V.P. Arch Dermatol Res (2009) 301: 87. doi:10.1007/s00403-008-0893-7

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.

Keywords

TNF-α Ultraviolet light Skin Fibroblast Keratinocyte 

Abbreviations

KCs

Keratinocytes

FBs

Fibroblasts

UVB

Ultraviolet B

TNF-α

Tumor necrosis factor-α

Copyright information

© US Government 2008

Authors and Affiliations

  1. 1.Department of DermatologyUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Medical ResearchPhiladelphia VAMCPhiladelphiaUSA

Personalised recommendations