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J. Biol. Chem., Vol. 280, Issue 45, 37536-37546, November 11, 2005

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Distinct Role of Calmodulin and Calmodulin-dependent Protein Kinase-II in Lipopolysaccharide and Tumor Necrosis Factor--mediated Suppression of Apoptosis and Antiapoptotic c-IAP2 Gene Expression in Human Monocytic Cells^*

Sasmita Mishra1, Jyoti P. Mishra1, Katrina Gee2, Dan C. McManus3, Eric C. LaCasse, and Ashok Kumar¶||4

From the Departments of ^¶Pathology ^|| and Laboratory Medicine and Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Infectious Disease and Vaccine Research Centre, Research Institute, Children's Hospital of Eastern Ontario, Ottawa, Ontario K1H 8L1, and Aegera Therapeutics Inc., Ottawa, Ontario K1H 8L1, Canada

Exposure of phagocytic cells to bacterial endotoxin (lipopolysaccharide; LPS) or inflammatory cytokines confers antiapoptotic survival signals; however, in the absence of the appropriate stimulus, monocytes are programmed to undergo apoptosis. Macrophage survival may thus influence inflammatory and immune responses and susceptibility to microbial pathogens. Herein, we demonstrate that LPS and the proinflammatory cytokine, tumor necrosis factor- (TNF-), enhance monocytic cell survival through the induction of the antiapoptotic c-IAP2 gene in a human promonocytic THP-1 cell line. We also investigated the role of upstream signaling molecules including the mitogen-activated protein kinases, phosphatidylinositol 3-kinase, and the calcium signaling pathways in the regulation of c-IAP2 expression and eventual survival of monocytic cells. Our results suggest that LPS and TNF--induced c-IAP2 expression was regulated by calmodulin (CaM) through the activation of calmodulin-dependent protein kinase-II (CaMKII). In addition, CaM and CaMKII regulated c-IAP2 expression in LPSand TNF--stimulated cells through NF-B activation. Moreover, the CaM/CaMKII pathway also regulated LPS- and TNF--mediated inhibition of apoptosis in these cells. Taken together, these results suggest that LPS- and TNF--induced c-IAP2 expression and its associated antiapoptotic survival signals in THP-1 cells are regulated selectively by CaM/CaMKII through NF-B activation.

Received for publication, May 5, 2005 , and in revised form, September 8, 2005.

^* This work was supported by grants from the Canadian Institutes of Health Research (to A. K.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1, 2, 3, 4.

¹ Supported by scholarships from the OGSST and OGS.

² Supported by fellowships from the Ontario HIV Treatment Network (OHTN) and Strategic Areas of Development, University of Ottawa.

³ Supported by a Natural Sciences and Engineering Research Council-Industrial Research Fellowship.

⁴ Recipient of the Career Scientist Award from the OHTN. To whom correspondence should be addressed: Division of Virology, Research Institute, Children's Hospital of Eastern Ontario, University of Ottawa, 401 Smyth Rd., Ottawa, Ontario K1H 8L1, Canada. Tel.: 613-737-7600 (ext. 3920); Fax: 613-738-4825; E-mail: akumar{at}uottawa.ca.

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