title: NF{kappa}B-dependent down-regulation of tumor necrosis factor receptor-associated proteins contributes to interleukin-1-mediated enhancement of ultraviolet B-induced apoptosis.
abstract: Activation of the transcription factor nuclear factor-kappaB (NFkappaB) by inflammatory cytokines like tumor necrosis (TNF) factor and interleukin-1 (IL-1) is generally associated with the induction of antiapoptotic pathways. Therefore, NFkappaB inhibits both intrinsically and extrinsically induced apoptosis and thus is regarded to act universally in an antiapoptotic fashion. Accordingly, activation of NFkappaB by IL-1 was shown to result in reduction of death ligand-induced apoptosis via up-regulation of antiapoptotic inhibitor of apoptosis proteins (IAPs). In contrast, apoptosis induced by ultraviolet-B radiation (UVB) was shown to be enhanced in an NFkappaB-dependent manner, indicating that NFkappaB can also act in a proapoptotic fashion. This study investigates the molecular mechanisms underlying IL-1-mediated enhancement of UVB-induced apoptosis. We show that NFkappaB activation in costimulation with UVB treatment results in repression of antiapoptotic genes and consequently in down-regulation of the respective proteins, like c-IAP, FLICE-inhibitory protein (FLIP), and some members of the TNF receptor-associated (TRAF)2 protein family. In parallel, TNFalpha is released, leading to activation of signaling pathways mediated by TNF receptor-1 (TNF-R1). Although TNF is well known to induce both proapoptotic and antiapoptotic effects, the down-regulated levels of TRAF-1, -2, and -6 proteins by IL-1 plus UVB action leads to a shift toward promotion of the proapoptotic pathway. In concert with the down-regulation of IAPs and FLIP, TNF-R1 activation as an additional proapoptotic stimulus now results in significant enhancement of UVB-induced apoptosis. Taken together, elucidation of the molecular mechanisms underlying IL-1-mediated enhancement of UVB-induced apoptosis revealed that NFkappaB does not exclusively act in an antiapoptotic fashion but may also mediate proapoptotic effects.
authors.affiliation: Department of Dermatology, University of Münster, Von-Esmarch Strasse 58, D-48149 Münster, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Pöppelmann
authors.forename: Kerstin
authors.initials: K
authors.lastname: Klimmek
authors.forename: Elwira
authors.initials: E
authors.lastname: Strozyk
authors.forename: Reinhard
authors.initials: R
authors.lastname: Voss
authors.forename: Thomas
authors.initials: T
authors.lastname: Schwarz
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kulms
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002277:Carcinoma / Q000188:drug therapy / Q000517:prevention & control; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000517:prevention & control; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism*; D014466:Ultraviolet Rays
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases