IκB Kinase Is an Essential Component of the Tpl2 Signaling Pathway

Abstract

IκB kinase (IKK), a key regulator of immune and inflammatory responses, is known as an effector kinase mediating activation of the transcription factor NF-κB. Whether IKK also participates in other signaling events is not known. Here we show that IKK serves as an essential component of a signaling pathway that involves activation of the Tpl2 kinase and its downstream targets, MEK1 and ERK. Inhibition of IKKβ in macrophages eliminates Tpl2 activation and ERK phosphorylation induced by lipopolysaccharide and tumor necrosis factor alpha. Using IKK-deficient murine fibroblasts, we further demonstrate that IKKβ, but not IKKα, is required for Tpl2 activation. Moreover, this novel function of IKKβ appears to involve phosphorylation and degradation of the Tpl2 inhibitor NF-κB1/p105. These findings suggest that IKKβ exerts its immune-regulatory functions by targeting different downstream signaling pathways.

We thank Millennium Pharmaceuticals, Inc., for the IKK inhibitor PS1145, Michael Karin for the MEFs and recombinant IKK, and N. R. Rice for the anti-p105 antibody.

This work was supported by research grant 1 R01 AI057555, awarded to S.-C.S. and M.Z., from the National Institutes of Health. M.W. and W.R. were supported by a predoctoral and postdoctoral training grant (5T32CA60395-10) from the National Institutes of Health.