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J. Biol. Chem., Vol. 280, Issue 29, 26825-26837, July 22, 2005

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Differential Involvement of Calmodulin-dependent Protein Kinase II-activated AP-1 and c-Jun N-terminal Kinase-activated EGR-1 Signaling Pathways in Tumor Necrosis Factor- and Lipopolysaccharide-induced CD44 Expression in Human Monocytic Cells^*

Jyoti P. Mishra, Sasmita Mishra, Katrina Gee¶, and Ashok Kumar||**

From the Departments of ^||Pathology and Laboratory Medicine, and Biochemistry, Microbiology and Immunology, University of Ottawa and the ^**Division of Virology and Molecular Immunology, Research Institute, Children's Hospital of Eastern Ontario, Ottawa, Ontario K1H 8L1, Canada

CD44 plays a crucial role in cell migration, inflammation, and immune responses. Alteration in the levels of CD44 expression on monocytic cells by endotoxins and immunoregulatory cytokines may modulate the migration of immune cells to inflammatory sites and the development of immune responses. Lipopolysaccharide (LPS) and the proinflammatory cytokine, tumor necrosis factor- (TNF-), act as important regulators of CD44 expression in human monocytic cells. We previously demonstrated that the c-Jun N-terminal kinase (JNK), a mitogen-activated protein kinase (MAPK), differentially regulated LPS- but not TNF--induced CD44 expression in monocytic cells. In this study, our results suggest that the calcium signaling pathway, in particular calmodulin (CaM) and CaM-dependent protein kinase II (CaMK-II), is involved in TNF-- but not LPS-induced CD44 expression. CD44 promoter analysis suggested the participation of distinct transcription factors AP-1 and Egr-1 in TNF-- and LPS-induced CD44 expression, respectively. Furthermore, TNF--induced CD44 expression was regulated by AP-1 through the activation of the CaMK-II pathway, whereas LPS-induced CD44 transcription was regulated specifically by Egr-1 through JNK activation. Overall, the results suggest the involvement of two distinct and independent signaling pathways involved in the regulation of CD44 transcription that may represent potential targets for anti-inflammatory agents capable of inhibiting CD44-mediated cell migration.

Received for publication, January 7, 2005 , and in revised form, May 9, 2005.

^* This work was supported in part by grants from the Cancer Research Society, Inc., Canada, the Natural Sciences and Engineering Research Council of Canada, and the Research Institute, Children's Hospital of Eastern Ontario (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.

Supported by fellowships from the Ontario Graduate Scholarship for Science and Technology and Ontario Graduate Scholarship programs.

^¶ Supported by fellowships from the Canadian Institute of Health Research and the Strategic Areas of Development from the University of Ottawa, Ottawa, Ontario, Canada.

Recipient of the Career Scientist Award from the Ontario HIV Treatment Network. 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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