Evidence that IL-6-type cytokine signaling in cardiomyocytes is inhibited by oxidative stress: Parthenolide targets JAK1 activation by generating ROS
✍ Scribed by Mazen Kurdi; George W. Booz
- Book ID
- 102312360
- Publisher
- John Wiley and Sons
- Year
- 2007
- Tongue
- English
- Weight
- 377 KB
- Volume
- 212
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Abstract
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) α 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. J. Cell. Physiol. 212: 424–431, 2007. © 2007 Wiley‐Liss, Inc.