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J. Biol. Chem., Vol. 281, Issue 43, 32175-32187, October 27, 2006

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Differential Engagement of Modules 1 and 4 of Vascular Cell Adhesion Molecule-1 (CD106) by Integrins 41 (CD49d/29) and M2 (CD11b/18) of Eosinophils^*

From the Departments of Biomolecular Chemistry and Medicine, University of Wisconsin, Madison, Wisconsin 53706-1532

We have studied adhesion of eosinophils to various forms of vascular cell adhesion molecule 1 (VCAM-1, CD106), an integrin counter-receptor implicated in eosinophil recruitment to the airway in asthma. Full-length 7d-VCAM-1, with seven immunoglobulin-like modules, contains integrin-binding sites in modules 1 and 4. The alternatively spliced six-module protein, 6d-VCAM-1, lacks module 4. In static assays, unactivated purified human blood eosinophils adhered similarly to recombinant soluble human 6d-VCAM-1 and 7d-VCAM-1 coated onto polystyrene microtiter wells. Further experiments, however, revealed differences in recognition of modules 1 and 4. Antibody blocking indicated that eosinophil adhesion to 6d-VCAM-1 or a VCAM-1 construct containing only modules 1–3, 1–3VCAM-1, is mediated by 41 (CD49d/29), whereas adhesion to a construct containing modules 4–7, 4–7VCAM-1, is mediated by both41 andM2 (CD11b/18). Inhibitors of phosphoinositide 3-kinase, which block adhesion of eosinophils mediated by M2, blocked adhesion to 4–7VCAM-1 but had no effect on adhesion to 6d-VCAM-1. Consistent with the antibody and pharmacological blocking experiments, eosinophilic leukemic cell lines lacking M2 did not adhere to 4–7VCAM-1 but did adhere to 6d-VCAM-1 or 1–3VCAM-1. Activation of eosinophils by interleukin (IL)-5 enhanced static adhesion to 6d-VCAM-1, 7d-VCAM-1, or 4–7VCAM-1; IL-5-enhanced adhesion to all 3 constructs was blocked by anti-M2. Adhesion of unstimulated eosinophils to 7d-VCAM-1 under flow conditions was inhibited by anti-4 or anti-M. IL-5 treatment decreased eosinophil adhesion to 7d-VCAM-1 under flow, and anti-M had the paradoxical effect of increasing adhesion. These results demonstrate that M2 modulates41-mediated eosinophil adhesion to VCAM-1 under both static and flow conditions.

Received for publication, January 31, 2006 , and in revised form, August 10, 2006.

^* This work was supported by Specialized Center of Research Grant HL56396, Hematology Training Grant RTH T32 HL007899, and General Clinical Research Center, National Institutes of Health Grant M01 RR03186. 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.

¹ To whom correspondence should be addressed: Dept. of Medicine, University of Wisconsin, 4285A Medical Sciences Center, 1300 University Ave., Madison, WI 53706-1532. Tel.: 608-262-1576; Fax: 608-263-4969; E-mail: dfmosher{at}facstaff.wisc.edu.

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