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p38 and ERK1/2 MAPKs mediate the interplay of TNF- and IL-10 in regulating oxidative stress and cardiac myocyte apoptosis

¹Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Center, and Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; and ²Biomolecular Science Center, University of Central Florida, Orlando, Florida

Submitted 7 August 2007 ; accepted in final form 26 September 2007

It is known that TNF- increases the production of ROS and decreases antioxidant enzymes, resulting in an increase in oxidative stress. IL-10 appears to modulate these effects. The present study investigated the role of p38 and ERK1/2 MAPKs in mediating the interplay of TNF- and IL-10 in regulating oxidative stress and cardiac myocyte apoptosis in Sprague-Dawley male rats. Isolated adult cardiac myocytes were exposed to TNF- (10 ng/ml), IL-10 (10 ng/ml), and IL-10 + TNF- (ratio 1) for 4 h. H₂O₂ (100 µM) as a positive control and the antioxidant Trolox (20 µmol/l) were used to confirm the involvement of oxidative stress. H₂O₂ treatment increased oxidative stress and apoptosis; TNF- mimicked these effects. Exposure to TNF- significantly increased ROS production, caused cell injury, and increased the number of apoptotic cells and Bax-to-Bcl-xl ratio. This change was associated with an increase in the phospho-p38 MAPK-to-total p38 MAPK ratio and a decrease in the phospho-ERK1/2-to-total ERK1/2 ratio. IL-10 treatment by itself had no effect on these parameters, but it prevented the above-listed changes caused by TNF-. The antioxidant Trolox modulated TNF--induced changes in Bax/Bcl-xl, cell injury, and MAPKs. Preexposure of cells to the p38 MAPK inhibitor SB-203580 prevented TNF--induced changes. Inhibition of the ERK pathway with PD-98059 attenuated the protective role of IL-10 against TNF--induced apoptosis. This study provides evidence in support of the essential role of p38 and ERK1/2 MAPKs in the interactive role of TNF- and IL-10 in cardiac myocyte apoptosis.

cell communication; heart failure; mitogen-activated protein kinase; signal transduction

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