A role for the extracellular signal-regulated kinase and p38 mitogen-activated protein kinases in interleukin-1 beta-stimulated delayed signal tranducer and activator of transcription 3 activation, atrial natriuretic factor expression, and cardiac myocyte morphology

We have demonstrated that two hypertrophic agents, interleukin-1 (IL-1 beta ) and leukemic inhibitory factor (LIF), altered cardiac myocyte morphology with striking similarity and prompted us to investigate the common actions of these cytokines. We compared the phosphorylation/activation of signal tr anducer and activator of transcription 3 (STAT3), extracellular signal-regu lated kinase (ERK), p38(MAPK), and c-Jun N-terminal kinase mitogen-activate d protein kinases (MAPKs). The phosphorylation of STAT3 by IL-1 beta was de layed (> 60 min), whereas the response to LIF was rapid (< 10 min) and tran sient. We confirmed that IL-1 beta potently stimulated all three MAPK subfa milies. In contrast, LIF promoted strong activation of ERKs, marginal activ ation of p38(MAPK), and no c-Jun N-terminal kinase activation. To test the roles of ERKs and p38(MAPK), myocytes were pretreated with PD98059 and SB20 3580. Either inhibitor alone prevented STAT3 phosphorylation, implicating E RKs and p38MAPK in the delayed STAT3 response to IL-1 beta. The interplay o f MAPKs and STAT3 phosphorylation in regulating IL-lp-stimulated hypertroph y was investigated by evaluating the effect of MAPK inhibitors on atrial na triuretic factor (ANF) expression and myocyte morphology. The specific inhi bition of either ERK or p38(MAPK) attenuated the IL-1 beta- or LIF-stimulat ed ANF expression by up to 70%. Inhibition was not further increased in the presence of both inhibitors. Furthermore, although individual inhibition o f ERK or p38(MAPK) did not affect morphology, co-treatment with both inhibi tors abrogated the hypertrophic morphology stimulated by IL-1 beta but not by LIF. Taken together, our data indicate that the activation of ERK and p3 8(MAPK) is essential in regulating a delayed STAT3 phosphorylation as well as changes in ANF expression and morphology that follow IL-1 beta treatment . Thus, the role of MAPKs in the hypertrophic response can be dictated at l east partly by the nature of the hypertrophic agent employed.