p38 MAPK and NF-kappa B collaborate to induce interleukin-6 gene expression and release - Evidence for a cytoprotective autocrine signaling pathway in a cardiac myocyte model system

In cardiac myocytes, the stimulation of p38 MAPK by the MAPKK, MKK6, activa tes the transcription factor, NF-kappa B, and protects cells from apoptosis . In the present study in primary neonatal rat cardiac myocytes, constituti vely active MKK6, MKK6(Glu), bound to I kappa B kinase (IKK)-beta and stimu lated its abilities to phosphorylate I kappa B and to activate NF-kappa B. MKK6(Glu) induced NF-kappa B-dependent interleukin (IL)-6 transcription and IL-6 release in a p38-dependent manner, IL-6 protected myocardial cells ag ainst apoptosis. Like IL-6, TNF-alpha, which activates both NF-kappa B and p38, also induced p38-dependent IL-6 expression and release and protected m yocytes from apoptotis. While TNF-alpha was relatively ineffective, IL-6 ac tivated myocardial cell STAT3 by about 8-fold, indicating a probable role f or this transcription factor in IL-6-mediated protection from apoptosis, TN F-alpha-mediated IL-6 induction was inhibited by a kinase-inactive form of the MAPKKK, TGF-beta activated protein kinase (Tak1), which is known to act ivate p38 and NF-kappa B in other cell types. Thus, by stimulating both p38 and NF-kappa B, Tak1-activating cytokines, like TNF-alpha, can induce IL-6 expression and release. Moreover, the myocyte-derived IL-6 may then functi on in an autocrine and/or paracrine fashion to augment myocardial cell surv ival during stresses that activate p38.