Journal of Biological Chemistry
Volume 282, Issue 49, 7 December 2007, Pages 35564-35573
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Mechanisms of Signal Transduction
TNFR1 and TNFR2 Signaling Interplay in Cardiac Myocytes*

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Tumor necrosis factor α (TNFα) plays a major role in chronic heart failure, signaling through two different receptor subtypes, TNFR1 and TNFR2. Our aim was to further delineate the functional role and signaling pathways related to TNFR1 and TNFR2 in cardiac myocytes. In cardiac myocytes isolated from control rats, TNFα induced ROS production, exerted a dual positive and negative action on [Ca2+] transient and cell fractional shortening, and altered cell survival. Neutralizing anti-TNFR2 antibodies exacerbated TNFα responses on ROS production and cell death, arguing for a major protective role of the TNFR2 pathway. Treatment with either neutralizing anti-TNFR1 antibodies or the glutathione precursor, N-acetylcysteine (NAC), favored the emergence of TNFR2 signaling that mediated a positive effect of TNFα on [Ca2+] transient and cell fractional shortening. The positive effect of TNFα relied on TNFR2-dependent activation of the cPLA2 activity, independently of serine 505 phosphorylation of the enzyme. Together with cPLA2 redistribution and AA release, TNFα induced a time-dependent phosphorylation of ERK, MSK1, PKCζ, CaMKII, and phospholamban on the threonine 17 residue. Taken together, our results characterized a TNFR2-dependent signaling and illustrated the close interplay between TNFR1 and TNFR2 pathways in cardiac myocytes. Although apparently predominant, TNFR1-dependent responses were under the yoke of TNFR2, acting as a critical limiting factor. In vivo NAC treatment proved to be a unique tool to selectively neutralize TNFR1-mediated effects of TNFα while releasing TNFR2 pathways.

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This work was supported by grants from the Institut National de la Santéet de la Recherche Médicale, the Université Paris-Val-de Marne, and the Association Française contre les Myopathies. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.