Proost, P; Struyf, S; Schols, D; Opdenakker, G; Sozzani, S; Allavena, P; Mantovani, A; Augustyns, K; Bal, G; Haemers, A; Lambeir, A; Scharpe, S; Van Damme, J; Meester, ID

Journal of Biological Chemistry [J. Biol. Chem.], vol. 274, no. 7, pp. 3988-3993, 12 Feb 1999

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 Gly sub(1)-Pro sub(2) dipeptide from the NH sub(2) terminus of macrophage-derived chemokine (MDC) but subsequently also the Tyr sub(3)-Gly sub(4) 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 Ca super(2+) through CC chemokine receptor 4 (CCR4) and was unable to desensitize for MDC-induced Ca super(2+)-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, NH sub(2)-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.