TAB1 modulates IL-1alpha mediated cytokine secretion but is dispensable for TAK1 activation.
Biochemical evidence indicates that TGF-beta-activated kinase 1 (TAK1), a key modulator of the inflammatory response, exists in a complex with various adaptor proteins including the TAK1 binding protein 1 (TAB1). However, the physiological importance of TAB1 in TAK1 activation, and in the subsequent induction of proinflammatory mediators, remains unclear. In this study, a critical role for TAK1 in IL-1alpha or TNFalpha stimulated MAPK and NFkappaB activation was confirmed by inhibition of the nuclear accumulation of NFkappaB p65 and phosphorylated forms of c-Jun and p38 following siRNA mediated TAK1 silencing. These effects were associated with significant reductions in IL-1alpha stimulated levels of secreted IL-6, IL-8, MCP-1 and GM-CSF. In contrast, IL-1alpha or TNFalpha dependent cellular redistribution of NFkappaB p65 and phosphorylated c-Jun and p38 was not affected by 80% siRNA mediated knockdown of TAB1 protein levels. Interestingly, IL-6, IL-8 and GM-CSF release from TAB1 siRNA transfected cells was significantly reduced following IL-1alpha treatment, but was unchanged after TNFalpha stimulation, suggesting differential roles for TAB1 in IL-1alpha and TNFalpha signalling pathways. These findings may imply an as yet unidentified role for TAB1 in the inflammatory response, which is independent of the activation of classical TAK1 associated signalling cascades.
Bertelsen
Malene
M
Department of Biological Sciences, AstraZeneca R&D, Scheelevägen 8, 221 87 Lund, Sweden.
Sanfridson
Annika
A
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D053582:Interleukin-1alpha / Q000494:pharmacology*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D053582:Interleukin-1alpha; D020930:MAP Kinase Kinase Kinases; D034741:RNA, Small Interfering; D000099151:MAP Kinase Kinase Kinase 7; C486300:TAB1 protein, human