Evidence that IL-6-type cytokine signaling in cardiomyocytes is inhibited by oxidative stress: parthenolide targets JAK1 activation by generating ROS.
Parthenolide, an anti-inflammatory compound, was reported to inhibit signal transducer and activator of transcription 3 (STAT3) activation by the interleukin (IL)-6-type cytokines by an undefined process, which was the focus of our study. Here we report that parthenolide reduced both basal and leukemia inhibitory factor (LIF)-induced STAT3 tyrosine 705 (Y705) phosphorylation in cardiomyocytes in a dose-dependent manner, but stimulated the MAP kinase signaling pathways. Activation of Janus kinase 1 (JAK1) tyrosine kinase was markedly reduced by parthenolide. Pretreatment with parthenolide inhibited JAK1-mediated phosphorylation of the LIF receptor subunits LIF receptor (LIFR) alpha and glycoprotein 130 (gp130), and reduced the LIF-induced increase in JAK1 association with both components. In addition, we documented that parthenolide, over the same concentration range, does not have a direct inhibitory effect on JAK1 autophosphorylation. However, we observed that parthenolide increased intracellular reactive oxygen species (ROS). Pretreatment with the antioxidant, N-acetyl-L-cysteine, completely suppressed the effect of parthenolide on JAK1 and STAT3. From these results, we conclude ROS generation in cardiomyocytes blocks STAT3 signaling of the IL-6-type cytokines by targeting JAK1. The finding that signaling by the IL-6-type cytokine may be redox-sensitive defines a novel mechanism of regulation that has implications for exploiting their therapeutic potential.
Kurdi
Mazen
M
The Division of Molecular Cardiology, The Cardiovascular Research Institute, The Texas A&M University System Health Science Center, Scott & White, Central Texas Veterans Health Care System, Temple, Texas 76504, USA.
Booz
George W
GW
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D053613:Janus Kinase 1 / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000378:metabolism; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507842:Lifr protein, rat; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; D012717:Sesquiterpenes; C494088:Stat3 protein, rat; D050822:Cytokine Receptor gp130; C002669:parthenolide; C507906:Jak1 protein, rat; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D000111:Acetylcysteine