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J. Biol. Chem., Vol. 282, Issue 20, 15238-15247, May 18, 2007

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Eotaxin Selectively Binds Heparin

AN INTERACTION THAT PROTECTS EOTAXIN FROM PROTEOLYSIS AND POTENTIATES CHEMOTACTIC ACTIVITY IN VIVO^*

From the Cancer and Vascular Biology Group, Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University, Building 54, Garran Road, Acton, Australian Capital Territory 0200, Australia

An important feature of chemokines is their ability to bind to the glycosaminoglycan (GAG) side chains of proteoglycans, predominately heparin and heparan sulfate. To date, all chemokines tested bind to immobilized heparin in vitro, as well as cell surface heparan sulfate in vitro and in vivo. These interactions play an important role in modulating the action of chemokines by facilitating the formation of stable chemokine gradients within the vascular endothelium and directing leukocyte migration, by protecting chemokines from proteolysis, by inducing chemokine oligomerization, and by facilitating transcytosis. Despite the importance of eotaxin in eosinophil differentiation and recruitment being well established, little is known about the interaction between eotaxin and GAGs and the functional consequences of such an interaction. Here we report that eotaxin binds selectively to immobilized heparin with high affinity (K_d = 1.23 x 10^-8 M), but not to heparan sulfate or a range of other GAGs. The interaction of eotaxin with heparin does not promote eotaxin oligomerization but protects eotaxin from proteolysis directly by plasmin and indirectly by cathepsin G and elastase. In vivo, co-administration of eotaxin and heparin is able to significantly enhance eotaxin-mediated eosinophil recruitment in a mouse air-pouch model. Furthermore, when heparin is co-administered with eotaxin at a concentration that does not normally result in eosinophil infiltration, eosinophil recruitment occurs. In contrast, heparin does not enhance eotaxin-mediated eosinophil chemotaxis in vitro, suggesting protease protection or haptotactic gradient formation as the mechanism by which heparin enhances eotaxin action in vivo. These results suggest a role for mast cell-derived heparin in the recruitment of eosinophils, reinforcing Th2 polarization of inflammatory responses.

Received for publication, August 22, 2006 , and in revised form, February 16, 2007.

^* This work was supported in part by a National Health and Medical Research Council (NHMRC) program grant. 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 Recipient of an NHMRC Peter Doherty Postdoctoral Fellowship.

² To whom correspondence should be addressed. Tel.: 61-2-6125-2604; Fax: 61-2-6125-2595; E-mail: christopher.parish{at}anu.edu.au.

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