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J. Biol. Chem. 278 (39): 37275-37287

© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

Tumor Necrosis Factor-{alpha} Induces Functionally Active Hyaluronan-adhesive CD44 by Activating Sialidase through p38 Mitogen-activated Protein Kinase in Lipopolysaccharide-stimulated Human Monocytic Cells*

Katrina Gee {ddagger} §, Maya Kozlowski ¶, and Ashok Kumar {ddagger} || ** {ddagger}{ddagger}

Departments of **Pediatrics and {ddagger}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 and Health Canada, Biologics and Genetic Therapies Directorate, Centre for Biologics Research, Ottawa, Ontario K1A 0L2, Canada

Abstract: Interaction of CD44, an adhesion molecule, with its ligand, hyaluronan (HA), in monocytic cells plays a critical role in cell migration, inflammation, and immune responses. Most cell types express CD44 but do not bind HA. The biological functions of CD44 have been attributed to the generation of the functionally active, HA-adhesive form of this molecule. Although lipopolysaccharide (LPS) and cytokines induce HA-adhesive CD44, the molecular mechanism underlying this process remains unknown. In this study, we show that LPS-induced CD44-mediated HA (CD44-HA) binding in monocytes is regulated by endogenously produced tumor necrosis factor (TNF)-{alpha} and IL-10. Furthermore, p38 mitogen-activated protein kinase (MAPK) activation was required for LPS- and TNF-{alpha}-induced, but not IL-10-induced, CD44-HA-binding in normal monocytes. To dissect the signaling pathways regulating CD44-HA binding independently of cross-regulatory IL-10-mediated effects, IL-10-refractory promonocytic THP-1 cells were employed. LPS-induced CD44-HA binding in THP-1 cells was regulated by endogenously produced TNF-{alpha}. Our results also suggest that lysosomal sialidase activation may be required for the acquisition of the HA-binding form of CD44 in LPS- and TNF-{alpha}-stimulated monocytic cells. Studies conducted to understand the role of MAPKs in the induction of sialidase activity revealed that LPS-induced sialidase activity was dependent on p42/44 MAPK-mediated TNF-{alpha} production. Blocking TNF-{alpha} production by PD98059, a p42/44 inhibitor, significantly reduced the LPS-induced sialidase activity and CD44-HA binding. Subsequently, TNF-{alpha}-mediated p38 MAPK activation induced sialidase activity and CD44-HA binding. Taken together, our results suggest that TNF-{alpha}-induced p38 MAPK activation may regulate the induction of functionally active HA-binding form of CD44 by activating sialidase in LPS-stimulated human monocytic cells.

Received for publication March 5, 2003. Revision received June 27, 2003.

* This work was supported 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 Medical Research Council of Canada and from the Strategic Areas of Development from the University of Ottawa, Ottawa, Ontario, Canada.

{ddagger}{ddagger} 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}

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