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

R. Craig, A. Larkin, A. M. Mingo, D. J. Thuerauf, C. Andrews, P. M. McDonough, C. C. Glembotski

Research output: Contribution to journalArticlepeer-review

299 Scopus citations

Abstract

In cardiac myocytes, the stimulation of p38 MAPK by the MAPKK, MKK6, activates the transcription factor, NF-κB, and protects cells from apoptosis. In the present study in primary neonatal rat cardiac myocytes, constitutively active MKK6, MKK6(Glu), bound to IκB kinase (IKK)-β and stimulated its abilities to phosphorylate IκB and to activate NF-κB. MKK6(Glu) induced NF-κB-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-α, which activates both NF-κB and p38, also induced p38-dependent IL-6 expression and release and protected myocytes from apoptotis. While TNF-α 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-α-mediated IL-6 induction was inhibited by a kinase-inactive form of the MAPKKK, TGF-β activated protein kinase (Tak1), which is known to activate p38 and NF-κB in other cell types. Thus, by stimulating both p38 and NF-κB, Tak1-activating cytokines, like TNF-α, 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.

Original languageEnglish (US)
Pages (from-to)23814-23824
Number of pages11
JournalJournal of Biological Chemistry
Volume275
Issue number31
DOIs
StatePublished - Aug 4 2000
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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