JAK2/STAT3, Not ERK1/2, Mediates Interleukin-6-induced Activation of Inducible Nitric-oxide Synthase and Decrease in Contractility of Adult Ventricular Myocytes

Abstract

Interleukin (IL)-6 decreases cardiac contractility via a nitric oxide (NO)-dependent pathway. However, mechanisms underlying IL-6-induced NO production remain unclear. JAK2/STAT3 and ERK1/2 are two well known signaling pathways activated by IL-6 in non-cardiac cells. However, these IL-6-activated pathways have not been identified in adult cardiac myocytes. In this study, we identified activation of these two pathways during IL-6 stimulation and examined their roles in IL-6-induced NO production and decrease in contractility of adult ventricular myocytes. IL-6 increased phosphorylation of STAT3 (at Tyr 705 ) and ERK1/2 (at Tyr 204 ) within 5 min that peaked at 15-30 min and returned to basal levels at 2 h. Phosphorylation of STAT3 was blocked by genistein, a protein tyrosine kinase inhibitor, and AG490, a JAK2 inhibitor, but not PD98059, an ERK1/2 kinase inhibitor. The phosphorylation of ERK1/2 was blocked by PD98059 and genistein but not AG490. Furthermore, IL-6 enhanced de novo synthesis of iNOS protein, increased NO production, and decreased cardiac contractility after 2 h of incubation. These effects were blocked by genistein and AG490 but not PD98059. We conclude that IL-6 activated independently the JAK2/STAT3 and ERK1/2 pathways, but only JAK2/ STAT3 signaling mediated the NO-associated decrease in contractility.

Cerium oxide nanoparticle treatment ameliorates peritonitis-induced diaphragm dysfunction

“…38 Similar to the mechanisms of the inflammatory response in cardiac muscle, we found that sepsis significantly increased Stat3 phosphorylation in diaphragm, and importantly, that this increase was attenuated with nanoparticle treatment ( Figure 4A). Likewise, increases in NO have been shown to directly impair contractile function in a number of different skeletal muscles including the diaphragm.…”

IL-6 induces regionally selective spinal cord injury in patients with the neuroinflammatory disorder transverse myelitis

“…Neutralization of CNS IL-6 attenuates traumatic spinal cord injury in rats and is associated with reduced iNOS activity (9). As has been seen in other tissues (10), IL-6 within the CNS may stimulate iNOS expression, resulting in the production of NO and leading to free radical-induced tissue injury (10).…”

“…Once formed, the IL-6/IL-6R/ gp130 complex stimulates the following 2 main signal transduction cascades that lead to activation of a number of transcription factors responsible for IL-6-mediated effects: JAK/STAT and Ras/MEK/ MAPK (11). IL-6-induced activation of the JAK2/STAT3 signaling pathway in cardiac myocytes results in activation of iNOS with subsequent NO production and decreased cardiac contractility (10).…”

Postischemic infusion of sivelestat sodium hydrate, a selective neutrophil elastase inhibitor, protects against myocardial stunning in swine

“…The serine protease, elastase, is a major contributor to neutrophil-mediated damage, and hydrolyzes the extracellular matrix components elastin, fibronectin and collagen types III and IV [23]. Neutrophil elastase induces production of cytokines which decreases cardiac contractility via a nitric oxide-dependent pathway [1], and produces toxic mediators such as reactive oxygen species (ROS) [24]. ROS is strongly implicated in the pathogenesis of myocardial stunning, necrosis, apoptosis and vascular dysfunction.…”

“…Neutrophil elastase is also known to induce production of cytokines, such as interleukin (IL)-6, which decreases cardiac contractility via a nitric oxide-dependent pathway [1]. Neutrophil elastase has been shown to be released in early stages of postischemic myocardial reperfusion in animal models [2], as well as during unstable angina attacks after myocardial infarction or cardiopulmonary bypass surgery in humans [3].…”