p38 MAPK and NF-κB 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, activates the transcription factor, NF-kappa B, and protects cells from apoptosis. In the present study in primary neonatal rat cardiac myocytes, constitutively active MKK6, MKK6(Glu), bound to I kappa B kinase (IKK)-beta and stimulated 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 against 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 myocytes from apoptotis. While TNF-alpha was relatively ineffective, IL-6 activated myocardial cell STAT3 by about 8-fold, indicating a probable role for this transcription factor in IL-6-mediated protection from apoptosis, TNF-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 activate 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 function in an autocrine and/or paracrine fashion to augment myocardial cell survival during stresses that activate p38.