p42/p44-MAPK and PI3K are sufficient for IL-6 family cytokines/gp130 to signal to hypertrophy and survival in cardiomyocytes in the absence of JAK/STAT activation.

Journal article

The effect of differential signalling by IL-6 and leukaemia inhibitory factor (LIF) which signal by gp130 homodimerisation or LIFRβ/gp130 heterodimerisation on survival and hypertrophy was studied in neonatal rat cardiomyocytes. Both LIF and IL-6 [in the absence of soluble IL-6 receptor (sIL-6Rα)] activated Erk1/2, JNK1/2, p38-MAPK and PI3K signalling peaking at 20min and induced cytoprotection against simulated ischemia-reperfusion injury which was blocked by the MEK1/2 inhibitor PD98059 but not the p38-MAPK inhibitor SB203580. In the absence of sIL-6R, IL-6 did not induce STAT1/3 phosphorylation, whereas IL-6/sIL-6R and LIF induced STAT1 and STAT3 phosphorylation. Furthermore, IL-6/sIL-6R induced phosphorylation of STAT1 Tyr(701) and STAT3 Tyr(705) were enhanced by SB203580. IL-6 and pheneylephrine (PE), but not LIF, induced cardiomyocyte iNOS expression and nitric oxide (NO) production. IL-6, LIF and PE induced cardiomyocyte hypertrophy, but with phenotypic differences in ANF and SERCA2 expression and myofilament organisation with IL-6 more resembling PE than LIF. Transfection of cardiomyocytes with full length or truncated chimaeric gp130 cytoplasmic domain/Erythropoietin receptor (EpoR) extracellular domain fusion constructs showed that the membrane proximal Box 1 and Box 2 containing region of gp130 was necessary and sufficient for MAPK and PI3K activation; hypertrophy; SERCA2 expression and iNOS/NO induction in the absence of JAK/STAT activation. In conclusion, IL-6 can signal in cardiomyocytes independent of sIL-6R and STAT1/3 and furthermore, that Erk1/2 and PI3K activation by IL-6 are both necessary and sufficient for induced cardioprotection. In addition, p38-MAPK may act as a negative feedback regulator of JAK/STAT activation in cardiomyocytes.

Authors: Fahmi, A; Smart, N; Punn, A; Jabr, R; Marber, M

• Journal: Cellular signalling
• Volume: 25
• Issue: 4
• Pages: 898-909
• Publication date: 2013-04-01
• DOI: 10.1016/j.cellsig.2012.12.008
• EISSN: 1873-3913
• ISSN: 0898-6568
• Language: English
• Keywords: Nitric Oxide Synthase Type II; Interleukin-6; Hypertrophy; Cells, Cultured; Animals; Leukemia Inhibitory Factor; Recombinant Fusion Proteins; Mitogen-Activated Protein Kinase 3; STAT3 Transcription Factor; Imidazoles; p38 Mitogen-Activated Protein Kinases; Mitogen-Activated Protein Kinase 1; Myocytes, Cardiac; Cytokine Receptor gp130; Signal Transduction; Pyridines; Humans; Reperfusion Injury; STAT1 Transcription Factor; Janus Kinases; Flavonoids; Phosphatidylinositol 3-Kinases; Nitric Oxide; Mice; Cell Survival; Receptors, Erythropoietin; Recombinant Proteins; Phosphorylation; Rats