HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 293/6/H3524    most recent 00919.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Dhingra, S. Articles by Singal, P. K. Search for Related Content PubMed PubMed Citation Articles by Dhingra, S. Articles by Singal, P. K.

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