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J Biol Chem, Vol. 274, Issue 7, 3988-3993, February 12, 1999

Truncation of Macrophage-derived Chemokine by CD26/ Dipeptidyl-Peptidase IV beyond Its Predicted Cleavage Site Affects Chemotactic Activity and CC Chemokine Receptor 4 Interaction

Paul Proost, Sofie Struyf, Dominique Schols, Ghislain Opdenakker, Silvano Sozzani^**, Paola Allavena^**, Alberto Mantovani^**, Koen Augustyns, Gunther Bal, Achiel Haemers, Anne-Marie Lambeir^§§, Simon Scharpé^§§, Jo Van Damme, and Ingrid De Meester^§§

From the  Laboratory of Molecular Immunology, and  Laboratory of Experimental Chemotherapy, Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium, ^** Laboratory of Immunology, Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, I-20157 Milan, Italy,  Laboratory of Pharmaceutical Chemistry, and ^§§ Laboratory of Clinical Biochemistry, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium

The serine protease CD26/dipeptidyl-peptidase IV (CD26/DPP IV) and chemokines are known key players in immunological processes. Surprisingly, CD26/DPP IV not only removed the expected Gly₁-Pro₂ dipeptide from the NH₂ terminus of macrophage-derived chemokine (MDC) but subsequently also the Tyr₃-Gly₄ dipeptide, generating MDC(5-69). This second cleavage after a Gly residue demonstrated that the substrate specificity of this protease is less restricted than anticipated. The unusual processing of MDC by CD26/DPP IV was confirmed on the synthetic peptides GPYGANMED (MDC(1-9)) and YGANMED (MDC(3-9)). Compared with intact MDC(1-69), CD26/DPP IV-processed MDC(5-69) had reduced chemotactic activity on lymphocytes and monocyte-derived dendritic cells, showed impaired mobilization of intracellular Ca²⁺ through CC chemokine receptor 4 (CCR4), and was unable to desensitize for MDC-induced Ca²⁺-responses in CCR4 transfectants. However, MDC(5-69) remained equally chemotactic as intact MDC(1-69) on monocytes. In contrast to the reduced binding to lymphocytes and CCR4 transfectants, MDC(5-69) retained its binding properties to monocytes and its anti-HIV-1 activity. Thus, NH₂-terminal truncation of MDC by CD26/DPP IV has profound biological consequences and may be an important regulatory mechanism during the migration of Th2 lymphocytes and dendritic cells to germinal centers and to sites of inflammation.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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