Tumour necrosis factor α and interleukin 1 signalling: do MAPKK kinases connect it all?

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Abstract

The potent pro-inflammatory cytokines tumour necrosis factor α (TNF-α) and interleukin 1 (il-1) are capable of triggering biologically similar effects through activation of the same set of transcription factors. Based on recent findings it is now becoming evident that certain members of the mitogen-activated protein kinase kinase (MAPKK) kinase protein family serve to integrate the individual signal transduction pathways that are initiated by the two cytokines into an array of parallel and common signalling cascades. The link between the receptor proximal, signal-specific intracellular events and the common MAPKK kinases appears to be made by a new class of proteins known as TNF receptor associated factors (TRAFs). Here, Jörg Eder describes how TNF-α and IL-1 use different, pathway-specific TRAFs to activate the same MAPKK kinase-controlled cascades.

Section snippets

Nuclear factor κB and activating protein 1

The two most prominent transcription factors responsible for the effects of TNF-α and IL-1 are nuclear factor κB (NF-κB) and activating protein 1 (AP-1). These factors mediate the induction of many proteins central to inflammatory processes and immune responses, such as cytokines, cell-adhesion molecules, growth factors, metalloproteinases and other proteins that participate in the production of prostaglandins, leukotrienes and NO (5, 6). Interestingly, glucocorticoids, which are potent

Link between NF-κB and AP-1 signal transduction pathways

Tumour necrosis factor α- and IL-1-like stimuli (such as UV irradiation, osmotic stress and lipopolysaccharide) induce the simultaneous activation of NF-κB, JNK and p38 kinase, and a connection between these MAP kinase pathways and NF-κB activation has now been established at the molecular level. The foundation for these discoveries was laid by D. Goeddel and co-workers studying the early events in TNF receptor signalling which led to the identification of a new family of proteins, termed

What the future might hold

At present, the TRAF–MAPKKK signal transduction level is one of the least-defined steps in TNF-α and IL-1 signalling. So far, direct binding of TRAFs to MAPKKs has only been demonstrated in one case: the TRAF2–NIK interaction, and it will be crucial to learn whether or not binding of TRAFs to MAPKKKs is indeed a general principle. Given that a catalytically inactive NIK mutant protein can block TNF-α- as well as IL-1-induced NF-κB activation, and that an inactive MEKK1 variant can inhibit

Acknowledgements

I am grateful to Max Schreier for many stimulating discussions and for his constant support for and interest in my work. I also thank Ralf Heilker and Hermann Gram for their critical reading of the manuscript.

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