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J. Biol. Chem., Vol. 279, Issue 34, 35201-35209, August 20, 2004

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Sialylated Complex-type N-Glycans Enhance the Signaling Activity of Soluble Intercellular Adhesion Molecule-1 in Mouse Astrocytes^*

Vivianne I. Otto, Thomas Schürpf¶, Gerd Folkers¶, and Richard D. Cummings

From the Department of Biochemistry and Molecular Biology, Oklahoma Center for Medical Glycobiology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104 and ^¶Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH), 8057 Zurich, Switzerland

Intercellular adhesion molecule-1 (ICAM-1) occurs as both a membrane and a soluble, secreted glycoprotein (sICAM-1). ICAM-1 on endothelial cells mediates leukocyte adhesion by binding to leukocyte function associated antigen-1 (LFA-1) and macrophage antigen-1 (Mac-1). Recombinant mouse sICAM-1 induces the production of macrophage inflammatory protein-2 (MIP-2) in mouse astrocytes by a novel LFA-1- and Mac-1-independent mechanism. Here we showed that N-glycan structures of sICAM-1 influence its ability to induce MIP-2 production. sICAM-1 expressed in Chinese hamster ovary (CHO) cells was a more potent inducer of MIP-2 production than sICAM-1 expressed in HEK 293 cells, suggesting that posttranslational modification of sICAM-1 could influence its signaling activity. To explore the roles of glycosylation in sICAM-1 activity, we expressed sICAM-1 in mutant CHO cell lines differing in glycosylation, including Lec2, Lec8, and Lec1 as well as in CHO cells cultured in the presence of the -mannosidase-I inhibitor kifunensine. Signaling activity of sICAM-1 lacking sialic acid was reduced 3-fold compared with sICAM-1 from CHO cells. The activity of sICAM-1 lacking both sialic acid and galactose was reduced 12-fold, whereas the activity of sICAM-1 carrying only high mannose-type N-glycans was reduced 12–26-fold. sICAM-1 glycoforms carrying truncated glycans retained full ability to bind to LFA-1 on leukocytes. Thus, sialylated and galactosylated complex-type N-glycans strongly enhanced the ability of sICAM-1 to induce MIP-2 production in astrocytes but did not alter its binding to LFA-1 on leukocytes. Glycosylation could therefore serve as a means to regulate specifically the signaling function of sICAM-1 in vivo.

Received for publication, May 4, 2004 , and in revised form, June 15, 2004.

^* This work was supported by a fellowship from the Swiss Foundation for Biomedical Fellowships (Schweizerische Stiftung für Medizinisch-Biologische Stipendien, SSMBS) (to V. I. O.) and by National Institutes of Health Grant RO1AI48075 (to R. D. C.). 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.

To whom correspondence should be addressed. Tel.: 01141-1-635-6062; Fax: 01141-1-635-6884; E-mail: vivianne.otto{at}pharma.ethz.ch.

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