The pleiotropic cytokine tumor necrosis factor- (TNF) controls the expression of multiple gene products in macrophages and plays an important role in host defense. TNF is recognized by the receptors, CD120a (p55) and CD120b (p75). Ligation of CD120a (p55) by TNF or by anti-receptor agonistic antibodies initiates signal transduction leading to the activation of mitogen-activated protein kinases (MAPKs) (p42 and p44). Phosphorylation and activation of MAPK are mediated by MAPK kinase (MEK), a family of Thr/Tyr kinases. In this study, we investigated the preferential involvement of the MEK isoforms MEK1 and MEK2 in the activation of p42 in mouse macrophages stimulated with TNF. Exposure of macrophages to TNF stimulated a time-dependent increase in the activity of MEK1 as measured by an in vitro kinase assay using kinase-inactive p42 (rMAPK) as substrate in the presence of -[P]ATP. Maximal activation of MEK1 was detected at 10 min poststimulation and coincided with maximal transphosphorylation of Tyr and Thr residues of rMAPK. By contrast, there was no evidence of MEK2 activation in macrophages in response to TNF. These data suggest that MEK1 is the preferred substrate for MEK kinase, the upstream kinase implicated in activation of the MAPK pathway in macrophages by TNF.

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