NFκB-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-B (NF B) by inflammatory cytokines like tumor necrosis (TNF) factor and interleukin-1 (IL-1) is generally associated with the induction of antiapoptotic pathways. Therefore, NF B inhibits both intrinsically and extrinsically induced apoptosis and thus is regarded to act universally in an antiapoptotic fashion. Accordingly, activation of NF B 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 NF B-dependent manner, indicating that NF B 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 NF B 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, TNF␣ 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 NF B does not exclusively act in an antiapoptotic fashion but may also mediate proapoptotic effects.

Differential effects of NF-κB on apoptosis induced by DNA-damaging agents: the type of DNA damage determines the final outcome

“…TNF-a induction seems to be NFkB-dependent, as it could be inhibited by the application of each of the three inhibitors of IkBa degradation and by overexpression of IkBsr ( Figure 1b). As published previously, costimulation of cells with IL-1 and death ligands (CD95 and TRAIL) did not result in any TNF-a release (Kothny-Wilkes et al, 1999;Po¨ppelmann et al, 2005), indicating that the strong NF-kB-dependent TNF-a expression may be linked to UVB-induced DNA damage.…”

“…Therefore, NF-kB was generally considered to act predominantly as a mediator of cell survival. Accordingly, costimulation of keratinocyte cell line HaCaT and epithelial carcinoma cell line KB with IL-1 inhibited TRAILinduced apoptosis in an NF-kB-dependent manner through upregulation of the antiapoptotic proteins cIAP and FLIP (Kothny-Wilkes et al, 1998Po¨ppelmann et al, 2005). The same effect was observed for CD95-induced apoptosis, supporting the notion that NF-kB antagonizes apoptosis induced by different stimuli.…”

“…Previous studies have demonstrated that the enhancement of apoptosis under these conditions is crucially linked to an enhanced release of TNF-a. However, addition of equivalent amounts of TNF-a to irradiated cells did not significantly enhance apoptosis, indicating that additional intracellular processes have to be involved (Po¨ppelmann et al, 2005). The enhanced sensitivity of UVB-irradiated cells to TNF-a was owing to a decreased expression of the antiapoptotic proteins FLIP and cIAP.…”

“…The enhanced sensitivity of UVB-irradiated cells to TNF-a was owing to a decreased expression of the antiapoptotic proteins FLIP and cIAP. In addition, TRAF-1, -2, and -6, signal transduction proteins involved in mediating cell survival via NF-kB activation, are downregulated upon UVB exposure and thus lead to a shift towards the proapoptotic pathway triggered by activation of TNF-R1 (Po¨ppelmann et al, 2005).…”

“…Therefore, UVB appears to cause the conversion of NF-kB from an antiapoptotic mediator to a mediator of proapoptotic pathways by changing its transcriptional properties, consequently enhancing UVB-induced apoptosis. The mechanism includes NFkB-mediated repression of antiapoptotic genes, like cIAP and FLIP, as well as repression of genes encoding TNF-R1-associated adaptor proteins TRAF-1, TRAF-2 and TRAF-6 (Po¨ppelmann et al, 2005). Another recent study revealed that TNF-a-mediated activation of NF-kB together with UVC or daunorubicin treatment manipulates NF-kB to interact with chromatin silencing histone deacetylases, thereby mediating specific gene repression of antiapoptotic genes, like cIAP and Bcl-2 (Campbell et al, 2004).…”