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J. Biol. Chem., Vol. 283, Issue 28, 19389-19399, July 11, 2008

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Matrix Metalloproteinase Processing of CXCL11/I-TAC Results in Loss of Chemoattractant Activity and Altered Glycosaminoglycan Binding^*

Jennifer H. Cox, Richard A. Dean, Clive R. Roberts, and Christopher M. Overall, Supported by a Canada Research Chair in Metalloproteinase Proteomics and Systems Biology and research grants from the Canadian Institutes of Health Research, the National Cancer Institute of Canada, and a Center Grant from the Michael Smith Research Foundation (University of British Columbia Center for Blood Research)¹

From the Departments of Biochemistry and Molecular Biology and Oral Biological and Medical Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada

The CXCR3 chemokine receptor regulates the migration of Th1 lymphocytes and responds to three ligands: CXCL9/MIG, CXCL10/IP-10, and CXCL11/I-TAC. We screened for potential regulation of T cell responses by matrix metalloproteinase (MMP) processing of these important chemokines. The most potent of the CXCR3 ligands, CXCL11, was identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry as a substrate of the PMN-specific MMP-8, macrophage-specific MMP-12, and the general leukocyte MMP-9. The 73-amino acid residue CXCL11 is processed at both the amino and carboxyl termini to generate CXCL11-(5–73), -(5–63), and -(5–58) forms. NH₂-terminal truncation results in loss of agonistic properties, as shown in calcium mobilization and chemotaxis experiments using CXCR3 transfectants and human T lymphocytes. Moreover, CXCL11-(5–73) is a CXCR3 antagonist and interestingly shows enhanced affinity to heparin. However, upon COOH-terminal truncation to position 58 there is loss of antagonist activity and heparin binding. Together this highlights an unexpected site for receptor interaction and that the carboxyl terminus is critical for glycosaminoglycan binding, an essential function for the formation of chemokine gradients in vivo. Hence, MMP activity might regulate CXCL11 tissue gradients in two ways. First, the potential of CXCL11-(5–73) to compete active CXCL11 from glycosaminoglycans might lead to the formation of an antagonistic haptotactic chemokine gradient. Second, upon further truncation, MMPs disperse the CXCL11 gradients in a novel way by proteolytic loss of a COOH-terminal GAG binding site. Hence, these results reveal potential new roles in down-regulating Th1 lymphocyte chemoattraction through MMP processing of CXCL11.

Received for publication, January 10, 2008 , and in revised form, March 27, 2008.

^* This work was supported in part by grants from the Michael Smith Foundation for Health Research (to J. H. C.), Natural Sciences and Engineering Research Council of Canada (to J. H. C.), and Canadian Institutes of Health Research Strategic Training Program STP-53877 (to J. H. 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.

¹ To whom correspondence should be addressed: 4.401 Life Sciences Institute, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada. Fax: 604-822-7742; E-mail: chris.overall{at}ubc.ca.

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