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W2005991858 abstract "Chemokines are key players in inflammation and infection. Natural forms of the C-X-C chemokine granulocyte chemotactic protein-2 (GCP-2) and the C-C chemokine regulated on activation normal T cell expressed and secreted (RANTES), which miss two NH2-terminal residues, including a Pro in the penultimate position, have been isolated from leukocytes or tumor cells. In chemotaxis and intracellular calcium mobilization assays, the truncation caused a reduction in the specific activity of RANTES but not of GCP-2. The serine protease CD26/dipeptidyl-peptidase IV (CD26/DPP IV) could induce this observed NH2-terminal truncation of GCP-2 and RANTES but not that of the monocyte chemotactic proteins MCP-1, MCP-2 and MCP-3. No significant difference in neutrophil activation was detected between intact and CD26/DPP IV-truncated GCP-2. In contrast to intact natural RANTES(1–68), which still chemoattracts monocytes at 10 ng/ml, CD26/DPP IV-truncated RANTES(3–68) was inactive at 300 ng/ml and behaved as a natural chemotaxis inhibitor. Compared with intact RANTES, only a 10-fold higher concentration of RANTES(3–68) induced a significant Ca2+ response. Furthermore, RANTES(3–68) inhibited infection of mononuclear cells by an M-tropic HIV-1 strain 5-fold more efficiently than intact RANTES. Thus, proteolytic processing of RANTES by CD26/DPP IV may constitute an important regulatory mechanism during anti-inflammatory and antiviral responses. Chemokines are key players in inflammation and infection. Natural forms of the C-X-C chemokine granulocyte chemotactic protein-2 (GCP-2) and the C-C chemokine regulated on activation normal T cell expressed and secreted (RANTES), which miss two NH2-terminal residues, including a Pro in the penultimate position, have been isolated from leukocytes or tumor cells. In chemotaxis and intracellular calcium mobilization assays, the truncation caused a reduction in the specific activity of RANTES but not of GCP-2. The serine protease CD26/dipeptidyl-peptidase IV (CD26/DPP IV) could induce this observed NH2-terminal truncation of GCP-2 and RANTES but not that of the monocyte chemotactic proteins MCP-1, MCP-2 and MCP-3. No significant difference in neutrophil activation was detected between intact and CD26/DPP IV-truncated GCP-2. In contrast to intact natural RANTES(1–68), which still chemoattracts monocytes at 10 ng/ml, CD26/DPP IV-truncated RANTES(3–68) was inactive at 300 ng/ml and behaved as a natural chemotaxis inhibitor. Compared with intact RANTES, only a 10-fold higher concentration of RANTES(3–68) induced a significant Ca2+ response. Furthermore, RANTES(3–68) inhibited infection of mononuclear cells by an M-tropic HIV-1 strain 5-fold more efficiently than intact RANTES. Thus, proteolytic processing of RANTES by CD26/DPP IV may constitute an important regulatory mechanism during anti-inflammatory and antiviral responses. Chemokines constitute a family of small proinflammatory cytokines with leukocyte chemotactic and activating properties. Depending on the position of the first two Cys, the chemokine family can be divided in C-C, C-X-C, C, and C-X3-C chemokines (1Baggiolini M. Dewald B. Moser B. Annu. Rev. Immunol. 1994; 55: 97-179Google Scholar, 2Baggiolini M. Dewald B. Moser B. Annu. Rev. Immunol. 1997; 15: 675-705Crossref PubMed Scopus (1976) Google Scholar, 3Taub D.D. Cytokine Growth Factor Rev. 1996; 7: 335-376Crossref Scopus (152) Google Scholar). Many C-X-C chemokines, such as interleukin-8 (IL-8), 1The abbreviations used are: IL, interleukin; [Ca2+]i, intracellular Ca2+ concentration; CCR, C-C chemokine receptor; CD26/DPP IV, dipeptidyl-peptidase IV; GCP-2, granulocyte chemotactic protein-2; MCP, monocyte chemotactic protein; MIP, macrophage inflammatory protein; RANTES, regulated on activation normal T cell expressed and secreted. 1The abbreviations used are: IL, interleukin; [Ca2+]i, intracellular Ca2+ concentration; CCR, C-C chemokine receptor; CD26/DPP IV, dipeptidyl-peptidase IV; GCP-2, granulocyte chemotactic protein-2; MCP, monocyte chemotactic protein; MIP, macrophage inflammatory protein; RANTES, regulated on activation normal T cell expressed and secreted. are chemotactic for neutrophils, whereas C-C chemokines, such as monocyte chemotactic protein-3 (MCP-3), are active on a variety of leukocytes, including monocytes, lymphocytes, eosinophils, basophils, natural killer cells, and dendritic cells.The NH2-terminal domain of chemokines is involved in receptor binding. NH2-terminal processing can either activate chemokines or render chemokines completely inactive. The C-X-C chemokine platelet basic protein becomes a natural neutrophil chemotactic peptide (neutrophil activating peptide-2) only after the enzymatic removal of 24 NH2-terminal residues (4Walz A. Baggiolini M. Biochem. Biophys. Res. Commun. 1989; 159: 969-975Crossref PubMed Scopus (80) Google Scholar, 5Van Damme J. Rampart M. Conings R. Decock B. Van Osselaer N. Willems J. Billiau A. Eur. J. Immunol. 1990; 20: 2113-2118Crossref PubMed Scopus (80) Google Scholar). Proteolytic cleavage of up to eight NH2-terminal residues from IL-8 results in an enhanced chemotactic activity, but further deletion of the Glu-Leu-Arg motif, which is located in front of the first Cys in all neutrophil chemotactic C-X-C chemokines, causes complete inactivation (6Clark-Lewis I. Schumacher C. Baggiolini M. Moser B. J. Biol. Chem. 1991; 266: 23128-23134Abstract Full Text PDF PubMed Google Scholar). Similar NH2-terminal proteolysis (up to eight amino acids) of another C-X-C chemokine, granulocyte chemotactic protein-2 (GCP-2), has no effect on its neutrophil chemotactic activity (7Proost P. Wuyts A. Conings R. Lenaerts J.-P. Billiau A. Opdenakker G. Van Damme J. Biochemistry. 1993; 32: 10170-10177Crossref PubMed Scopus (71) Google Scholar). However, the NH2 terminus has been reported to be essential for MCPs to retain their biological activity. The synthetical C-C chemokines MCP-1, MCP-3, and RANTES missing the eight or nine NH2-terminal amino acids are inactive on monocytes and are useful as receptor inhibitors (8Gong J.-H. Uguccioni M. Dewald B. Baggiolini M. Clark-Lewis I. J. Biol. Chem. 1996; 271: 10521-10527Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, 9Gong J.H. Clark-Lewis I. J. Exp. Med. 1995; 181: 631-640Crossref PubMed Scopus (266) Google Scholar). Extension of RANTES with one methionine results in complete inactivation of the molecule, and Met-RANTES behaves as an inhibitor for authentic RANTES (10Proudfoot A.E. Power C.A. Hoogewerf A.J. Montjovent M.O. Borlat F. Offord R.E. Wells T.N. J. Biol. Chem. 1996; 271: 2599-2603Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar).In this report, we describe the physiological occurrence of natural forms of human GCP-2 and RANTES missing the first two amino acids, and we give direct evidence that dipeptidyl-peptidase IV (DPP IV; EC3.4.14.5) is capable of cleaving these chemokines at their NH2 terminus. The exopeptidase DPP IV is present as a membrane-associated ectoenzyme on lymphocytes, epithelial cells, and endothelial cells and occurs in soluble form in body fluids, such as plasma, urine, and seminal fluid (11Fleischer B. Immunol. Today. 1994; 15: 180-184Abstract Full Text PDF PubMed Scopus (53) Google Scholar). In the hematopoietic system, DPP IV was identified as the activation antigen CD26. A subpopulation of memory (CD45RO+) T cells with a high surface density of CD26 is responsible for the proliferation in response to recall antigenin vitro (12Vanham G. Kestens L. De Meester I. Vingerhoets J. Penne G. Vanhoof G. Scharpé S. Heyligen H. Bosmans E. Ceuppens J.L. J. Acquired Immune Defic. Syndr. 1993; 6: 749-757PubMed Google Scholar). CD26/DPP IV is a highly specific aminopeptidase, cleaving off dipeptides from the NH2terminus of peptides with a Pro, Hyp, or Ala at the penultimate position (11Fleischer B. Immunol. Today. 1994; 15: 180-184Abstract Full Text PDF PubMed Scopus (53) Google Scholar). A number of cytokines, and among these, several chemokines, share an Xaa-Pro sequence at their NH2 terminus (13Vanhoof G. Goossens F. De Meester I. Hendriks D. Scharpé S. FASEB J. 1995; 9: 736-744Crossref PubMed Scopus (380) Google Scholar). The NH2-terminal Xaa-Pro may not only contribute to the receptor binding and/or signaling function, but may also serve as a structural protection against nonspecific proteolytic degradation. Inhibition of the enzymatic activity of CD26/DPP IV has been reported to suppress T cell proliferation in vitro (14Schön E. Jahn S. Kiessig S.T. Demuth H.U. Neubert K. Barth A. Von Baehr R. Ansorge S. Eur. J. Immunol. 1987; 17: 1821-1826Crossref PubMed Scopus (151) Google Scholar), to decrease antibody production in mice (15Kubota T. Flentke G.R. Bachovchin W.W. Stollar B.D. Clin. Exp. Immunol. 1992; 89: 192-197Crossref PubMed Scopus (100) Google Scholar), and to prolong cardiac allograft survival in rat recipients (16Korom S. De Meester I. Stadlbauer T.H.W. Chandraker A. Schaub M. Sayegh M.H. Belyaev A. Haemers A. Scharpé S. KupiecWeglinski J.W. Transplantation. 1997; 63: 1495-1500Crossref PubMed Scopus (95) Google Scholar). However, the natural substrates targeted by CD26/DPP IV in the immune system are unknown.Recently, a role for both CD26/DPP IV and C-C chemokines,i.e. RANTES and the macrophage inflammatory proteins MIP-1α and MIP-1β, has been postulated during HIV-1 infection with macrophage-tropic (M-tropic) HIV-1 strains (17Oravecz T. Roderiquez G. Koffi J. Wang J. Ditto M. Bou-Habib D.C. Lusso P. Norcross M.A. Nat. Med. 1995; 1: 919-926Crossref PubMed Scopus (61) Google Scholar, 18Cocchi F. DeVico A.L. Garzino-Demo A. Arya S.K. Gallo R.C. Lusso P. Science. 1995; 270: 1811-1815Crossref PubMed Scopus (2620) Google Scholar). RANTES, MIP-1α, and MIP-1β inhibit HIV-1 infection by competing for the same seven transmembrane-spanning G protein-coupled C-C chemokine receptor 5 (CCR5) (19Murphy P.M. Cytokine Growth Factor Rev. 1996; 7: 47-64Crossref PubMed Scopus (281) Google Scholar, 20Premack B.A. Schall T.J. Nat. Med. 1996; 2: 1174-1178Crossref PubMed Scopus (572) Google Scholar, 21D'Souza M.P. Harden V.A. Nat. Med. 1996; 2: 1293-1300Crossref PubMed Scopus (271) Google Scholar). The observation that CD26/DPP IV reduces the chemotactic efficacy of RANTES while increasing its antiviral potency brings new insights into the mechanisms underlying the role of CD26/DPP IV during HIV-1 infection and inflammation.DISCUSSIONLimited NH2-terminal truncation of chemokines has different consequences for their biological potency resulting in either increased (C-X-C chemokines) or decreased (C-C chemokines) specific activity (4Walz A. Baggiolini M. Biochem. Biophys. Res. Commun. 1989; 159: 969-975Crossref PubMed Scopus (80) Google Scholar, 5Van Damme J. Rampart M. Conings R. Decock B. Van Osselaer N. Willems J. Billiau A. Eur. J. Immunol. 1990; 20: 2113-2118Crossref PubMed Scopus (80) Google Scholar, 6Clark-Lewis I. Schumacher C. Baggiolini M. Moser B. J. Biol. Chem. 1991; 266: 23128-23134Abstract Full Text PDF PubMed Google Scholar, 7Proost P. Wuyts A. Conings R. Lenaerts J.-P. Billiau A. Opdenakker G. Van Damme J. Biochemistry. 1993; 32: 10170-10177Crossref PubMed Scopus (71) Google Scholar, 8Gong J.-H. Uguccioni M. Dewald B. Baggiolini M. Clark-Lewis I. J. Biol. Chem. 1996; 271: 10521-10527Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, 9Gong J.H. Clark-Lewis I. J. Exp. Med. 1995; 181: 631-640Crossref PubMed Scopus (266) Google Scholar, 10Proudfoot A.E. Power C.A. Hoogewerf A.J. Montjovent M.O. Borlat F. Offord R.E. Wells T.N. J. Biol. Chem. 1996; 271: 2599-2603Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar). During the purification of GCP-2 and RANTES from natural sources, we detected significant quantities (more than 50% of the chemokine content) of NH2-terminally truncated variants missing the first two amino acids (Gly-Pro and Ser-Pro for GCP-2 and RANTES, respectively). We tested whether the exopeptidase CD26/DPP IV was able to process these and other chemokines with a penultimate Pro at their NH2 terminus and whether this cleavage resulted in an altered biological activity. Although the occurrence of the NH2-terminal Xaa-Pro motif as a target for CD26/DPP IV was observed several years ago, the failure of processing mature IL-1α, IL-1β, IL-2, and other cytokines by CD26/DPP IV indicated that peptides become less susceptible to cleavage by CD26/DPP IV with increasing length (11Fleischer B. Immunol. Today. 1994; 15: 180-184Abstract Full Text PDF PubMed Scopus (53) Google Scholar, 29Hoffmann T. Faust J. Neubert K. Ansorge S. FEBS Lett. 1993; 336: 61-64Crossref PubMed Scopus (115) Google Scholar). Indeed, the largest peptide (44 amino acids) reported to be sensitive to NH2-terminal truncation by CD26/DPP IV is growth hormone-releasing hormone (30Frohman L.A. Downs T. Heimer E. Felix A. J. Clin. Invest. 1989; 83: 1533-1540Crossref PubMed Scopus (161) Google Scholar).In this study, two chemokines of about 70 residues with Pro at the penultimate NH2-terminal position, i.e. the C-X-C chemokine GCP-2 and the C-C chemokine RANTES, were processed by CD26/DPP IV, but the C-C chemokines MCP-1, MCP-2, and MCP-3 were resistant to degradation by the enzyme. Earlier observations that naturally truncated froms of MCP-1, MCP-2, or MCP-3, missing two NH2-terminal amino acids, were not isolated from various cellular sources (22Proost P. Wuyts A. Conings R. Lenaerts J.-P. Put W. Van Damme J. Methods: Companion Methods in Enzymol. 1996; 10: 82-92Crossref Scopus (27) Google Scholar) confirm the specificity of CD26/DPP IV. Resistance of MCP-2 to CD26/DPP IV is a consequence of the presence of the NH2-terminal pyroglutamic acid, because recombinant MCP-2 with an NH2-terminal Gln was cleaved by CD26/DPP IV (data not shown). The importance of the NH2-terminal residues has been illustrated by chemical synthesis of truncated MCP-1 and MCP-3, which are devoid of monocyte chemotactic activity (8Gong J.-H. Uguccioni M. Dewald B. Baggiolini M. Clark-Lewis I. J. Biol. Chem. 1996; 271: 10521-10527Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, 9Gong J.H. Clark-Lewis I. J. Exp. Med. 1995; 181: 631-640Crossref PubMed Scopus (266) Google Scholar). Truncation of GCP-2 with CD26/DPP IV had no significant effect on the chemotactic and Ca2+-releasing capacity of the chemokine. In contrast, a 10–100-fold decreased monocyte chemotactic and intracellular Ca2+-releasing activity was detected with RANTES(3–68) processed by CD26/DPP IV. However, RANTES and RANTES(3–68) were reported to be equipotent eosinophil chemotactic proteins (31Noso N. Sticherling M. Bartels J. Mallet A.I. Christophers E. Schröder J.-M. J. Immunol. 1996; 156: 1946-1953PubMed Google Scholar). Expression of different RANTES receptors,i.e. CCR3 on eosinophils compared with CCR1 and CCR5 on mononuclear cells (3Taub D.D. Cytokine Growth Factor Rev. 1996; 7: 335-376Crossref Scopus (152) Google Scholar, 19Murphy P.M. Cytokine Growth Factor Rev. 1996; 7: 47-64Crossref PubMed Scopus (281) Google Scholar), may explain the different interaction of RANTES(3–68) with both cell types. In addition to monocytes, also memory type CD45RO+ T cells, which express CCR1, CCR5, and CD26, are important target cells for RANTES (32Wu B.L. Paxton W.A. Kassam N. Ruffing N. Rottman J.B. Sullivan N. Choe H. Sodroski J. Newman W. Koup R.A. MacKay C.R. J. Exp. Med. 1997; 185: 1681-1691Crossref PubMed Scopus (638) Google Scholar, 33Schall T.J. Bacon K. Toy K.J. Goeddel D.V. Nature. 1990; 347: 669-671Crossref PubMed Scopus (1255) Google Scholar). In view of these observations, a physical proximity between RANTES and CD26/DPP IV seems feasible, and therefore, the processing of RANTES by CD26/DPP IV is likely to be of biological significance.When tested as a RANTES inhibitor, 1 μg/ml of inactive RANTES(3–68) was able to inhibit monocyte chemotaxis toward 100 ng/ml and 300 ng/ml of intact RANTES. In Ca2+ mobilization experiments, 300 ng/ml of RANTES(3–68) only partially desensitized for a response toward intact RANTES. These results suggest that RANTES(3–68) binds to at least one receptor and that the interaction of RANTES(3–68) with the receptor(s) is sufficient for partial signal transduction (increase of the [Ca2+]i) but not for chemotaxis.Recently, chemokines, their receptors, and CD26/DPP IV have been linked to HIV-1-infection. Concerning the role of CD26/DPP IV in HIV-infection, contrasting reports have been published. A positive correlation between the level of CD26/DPP IV-expression and the susceptibility to infection with M-tropic HIV-1 viruses was found (17Oravecz T. Roderiquez G. Koffi J. Wang J. Ditto M. Bou-Habib D.C. Lusso P. Norcross M.A. Nat. Med. 1995; 1: 919-926Crossref PubMed Scopus (61) Google Scholar), whereas this correlation could not be detected for T-tropic viruses (34Morimoto C. Lord C.I. Zhang C. Duke-Cohan J.S. Letvin N.L. Schlossman S.F. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 9960-9964Crossref PubMed Scopus (73) Google Scholar). Moreover, CD26/DPP IV was described as a cofactor for HIV entry in CD4+ cells (35Callebaut C. Krust B. Jacotot E. Hovanessian A.G. Science. 1993; 262: 2045-2050Crossref PubMed Scopus (207) Google Scholar). In contrast, CD26/DPP IV+cells were found to be less susceptible to HIV infection than CD26/DPP IV− cells (34Morimoto C. Lord C.I. Zhang C. Duke-Cohan J.S. Letvin N.L. Schlossman S.F. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 9960-9964Crossref PubMed Scopus (73) Google Scholar). A specific decrease in CD26/DPP IV-expression was reported upon HIV-1 infection of cells with M-tropic, but not T-tropic viruses (17Oravecz T. Roderiquez G. Koffi J. Wang J. Ditto M. Bou-Habib D.C. Lusso P. Norcross M.A. Nat. Med. 1995; 1: 919-926Crossref PubMed Scopus (61) Google Scholar), and both the absolute number and the proportion of CD26+ T cells were decreased in HIV-infected persons (12Vanham G. Kestens L. De Meester I. Vingerhoets J. Penne G. Vanhoof G. Scharpé S. Heyligen H. Bosmans E. Ceuppens J.L. J. Acquired Immune Defic. Syndr. 1993; 6: 749-757PubMed Google Scholar).Several chemokines, including RANTES, were identified as inhibitors of HIV-1 infection (18Cocchi F. DeVico A.L. Garzino-Demo A. Arya S.K. Gallo R.C. Lusso P. Science. 1995; 270: 1811-1815Crossref PubMed Scopus (2620) Google Scholar). The use of CCR5 as a coreceptor by M-tropic viruses explains the inhibitory effect of the C-C chemokines RANTES, MIP-1α, and MIP-1β on HIV-1 infection (19Murphy P.M. Cytokine Growth Factor Rev. 1996; 7: 47-64Crossref PubMed Scopus (281) Google Scholar, 20Premack B.A. Schall T.J. Nat. Med. 1996; 2: 1174-1178Crossref PubMed Scopus (572) Google Scholar, 21D'Souza M.P. Harden V.A. Nat. Med. 1996; 2: 1293-1300Crossref PubMed Scopus (271) Google Scholar). Co-expression of CD26/DPP IV and CCR5 (32Wu B.L. Paxton W.A. Kassam N. Ruffing N. Rottman J.B. Sullivan N. Choe H. Sodroski J. Newman W. Koup R.A. MacKay C.R. J. Exp. Med. 1997; 185: 1681-1691Crossref PubMed Scopus (638) Google Scholar) could therefore explain the specific decrease of CD26+CD4+ cells during HIV infection. Recent reports on chemically synthesized RANTES(9–68), missing six extra NH2-terminal residues compared with RANTES(3–68), have shown a reduction of the anti-HIV activity of RANTES (36Arenzana-Seisdedos F. Virelizier J.-L. Rousset D. Clark-Lewis I. Loetscher P. Moser B. Baggiolini M. Nature. 1996; 383: 400Crossref PubMed Scopus (265) Google Scholar). RANTES(9–68) also functioned as a chemokine inhibitor, but about 10-fold higher amounts, compared with intact RANTES, were necessary to obtain a comparable anti-HIV-1 activity. NH2-terminally altered amino-oxypentane-RANTES also acts as a chemotaxis inhibitor and, in contrast to RANTES(9–68), was more efficient as an inhibitor of HIV-1 infection than intact RANTES (37Simmons G. Clapham P.R. Picard L. Offord R.E. Rosenkilde M.M. Schwartz T.W. Buser R. Wells T.N.C. Proudfoot A.E.I. Science. 1997; 276: 276-279Crossref PubMed Scopus (591) Google Scholar). Thus, minor modifications of RANTES at the NH2 terminus are detrimental to its chemotactic activity and alter its anti-HIV activity. Compared with intact RANTES, RANTES(3–68), generated by CD26/DPP IV cleavage, is a more efficient inhibitor of HIV-1 infection of peripheral blood mononuclear cells with M-tropic strains. At the same time, RANTES(3–68), which is a much weaker chemotaxis agonist compared with intact RANTES, can provide negative feedback to weaken the inflammatory response. Although it is at present impossible to discriminate between RANTES(1–68) and RANTES(3–68) in clinical samples, studies on the in vivo balance between both RANTES forms may provide interesting information on the (patho-)physiological role of RANTES(3–68).In conclusion, we have isolated naturally occurring forms of the chemokines GCP-2 and RANTES, missing their NH2-terminal Xaa-Pro motif. We demonstrated that CD26/DPP IV is able to cleave chemokines in vitro into these NH2-terminally truncated forms. Although truncated and intact GCP-2 are equally active, RANTES(3–68) becomes a natural chemotaxis inhibitor and is a more potent inhibitor of HIV-1-infection than intact RANTES. RANTES is the first cytokine reported, of which the biological activity can be modified by CD26/DPP IV. This finding may lead to novel insights on the role of this specific peptidase not only in HIV-infection but also in inflammatory processes and immune responses. Chemokines constitute a family of small proinflammatory cytokines with leukocyte chemotactic and activating properties. Depending on the position of the first two Cys, the chemokine family can be divided in C-C, C-X-C, C, and C-X3-C chemokines (1Baggiolini M. Dewald B. Moser B. Annu. Rev. Immunol. 1994; 55: 97-179Google Scholar, 2Baggiolini M. Dewald B. Moser B. Annu. Rev. Immunol. 1997; 15: 675-705Crossref PubMed Scopus (1976) Google Scholar, 3Taub D.D. Cytokine Growth Factor Rev. 1996; 7: 335-376Crossref Scopus (152) Google Scholar). Many C-X-C chemokines, such as interleukin-8 (IL-8), 1The abbreviations used are: IL, interleukin; [Ca2+]i, intracellular Ca2+ concentration; CCR, C-C chemokine receptor; CD26/DPP IV, dipeptidyl-peptidase IV; GCP-2, granulocyte chemotactic protein-2; MCP, monocyte chemotactic protein; MIP, macrophage inflammatory protein; RANTES, regulated on activation normal T cell expressed and secreted. 1The abbreviations used are: IL, interleukin; [Ca2+]i, intracellular Ca2+ concentration; CCR, C-C chemokine receptor; CD26/DPP IV, dipeptidyl-peptidase IV; GCP-2, granulocyte chemotactic protein-2; MCP, monocyte chemotactic protein; MIP, macrophage inflammatory protein; RANTES, regulated on activation normal T cell expressed and secreted. are chemotactic for neutrophils, whereas C-C chemokines, such as monocyte chemotactic protein-3 (MCP-3), are active on a variety of leukocytes, including monocytes, lymphocytes, eosinophils, basophils, natural killer cells, and dendritic cells. The NH2-terminal domain of chemokines is involved in receptor binding. NH2-terminal processing can either activate chemokines or render chemokines completely inactive. The C-X-C chemokine platelet basic protein becomes a natural neutrophil chemotactic peptide (neutrophil activating peptide-2) only after the enzymatic removal of 24 NH2-terminal residues (4Walz A. Baggiolini M. Biochem. Biophys. Res. Commun. 1989; 159: 969-975Crossref PubMed Scopus (80) Google Scholar, 5Van Damme J. Rampart M. Conings R. Decock B. Van Osselaer N. Willems J. Billiau A. Eur. J. Immunol. 1990; 20: 2113-2118Crossref PubMed Scopus (80) Google Scholar). Proteolytic cleavage of up to eight NH2-terminal residues from IL-8 results in an enhanced chemotactic activity, but further deletion of the Glu-Leu-Arg motif, which is located in front of the first Cys in all neutrophil chemotactic C-X-C chemokines, causes complete inactivation (6Clark-Lewis I. Schumacher C. Baggiolini M. Moser B. J. Biol. Chem. 1991; 266: 23128-23134Abstract Full Text PDF PubMed Google Scholar). Similar NH2-terminal proteolysis (up to eight amino acids) of another C-X-C chemokine, granulocyte chemotactic protein-2 (GCP-2), has no effect on its neutrophil chemotactic activity (7Proost P. Wuyts A. Conings R. Lenaerts J.-P. Billiau A. Opdenakker G. Van Damme J. Biochemistry. 1993; 32: 10170-10177Crossref PubMed Scopus (71) Google Scholar). However, the NH2 terminus has been reported to be essential for MCPs to retain their biological activity. The synthetical C-C chemokines MCP-1, MCP-3, and RANTES missing the eight or nine NH2-terminal amino acids are inactive on monocytes and are useful as receptor inhibitors (8Gong J.-H. Uguccioni M. Dewald B. Baggiolini M. Clark-Lewis I. J. Biol. Chem. 1996; 271: 10521-10527Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, 9Gong J.H. Clark-Lewis I. J. Exp. Med. 1995; 181: 631-640Crossref PubMed Scopus (266) Google Scholar). Extension of RANTES with one methionine results in complete inactivation of the molecule, and Met-RANTES behaves as an inhibitor for authentic RANTES (10Proudfoot A.E. Power C.A. Hoogewerf A.J. Montjovent M.O. Borlat F. Offord R.E. Wells T.N. J. Biol. Chem. 1996; 271: 2599-2603Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar). In this report, we describe the physiological occurrence of natural forms of human GCP-2 and RANTES missing the first two amino acids, and we give direct evidence that dipeptidyl-peptidase IV (DPP IV; EC3.4.14.5) is capable of cleaving these chemokines at their NH2 terminus. The exopeptidase DPP IV is present as a membrane-associated ectoenzyme on lymphocytes, epithelial cells, and endothelial cells and occurs in soluble form in body fluids, such as plasma, urine, and seminal fluid (11Fleischer B. Immunol. Today. 1994; 15: 180-184Abstract Full Text PDF PubMed Scopus (53) Google Scholar). In the hematopoietic system, DPP IV was identified as the activation antigen CD26. A subpopulation of memory (CD45RO+) T cells with a high surface density of CD26 is responsible for the proliferation in response to recall antigenin vitro (12Vanham G. Kestens L. De Meester I. Vingerhoets J. Penne G. Vanhoof G. Scharpé S. Heyligen H. Bosmans E. Ceuppens J.L. J. Acquired Immune Defic. Syndr. 1993; 6: 749-757PubMed Google Scholar). CD26/DPP IV is a highly specific aminopeptidase, cleaving off dipeptides from the NH2terminus of peptides with a Pro, Hyp, or Ala at the penultimate position (11Fleischer B. Immunol. Today. 1994; 15: 180-184Abstract Full Text PDF PubMed Scopus (53) Google Scholar). A number of cytokines, and among these, several chemokines, share an Xaa-Pro sequence at their NH2 terminus (13Vanhoof G. Goossens F. De Meester I. Hendriks D. Scharpé S. FASEB J. 1995; 9: 736-744Crossref PubMed Scopus (380) Google Scholar). The NH2-terminal Xaa-Pro may not only contribute to the receptor binding and/or signaling function, but may also serve as a structural protection against nonspecific proteolytic degradation. Inhibition of the enzymatic activity of CD26/DPP IV has been reported to suppress T cell proliferation in vitro (14Schön E. Jahn S. Kiessig S.T. Demuth H.U. Neubert K. Barth A. Von Baehr R. Ansorge S. Eur. J. Immunol. 1987; 17: 1821-1826Crossref PubMed Scopus (151) Google Scholar), to decrease antibody production in mice (15Kubota T. Flentke G.R. Bachovchin W.W. Stollar B.D. Clin. Exp. Immunol. 1992; 89: 192-197Crossref PubMed Scopus (100) Google Scholar), and to prolong cardiac allograft survival in rat recipients (16Korom S. De Meester I. Stadlbauer T.H.W. Chandraker A. Schaub M. Sayegh M.H. Belyaev A. Haemers A. Scharpé S. KupiecWeglinski J.W. Transplantation. 1997; 63: 1495-1500Crossref PubMed Scopus (95) Google Scholar). However, the natural substrates targeted by CD26/DPP IV in the immune system are unknown. Recently, a role for both CD26/DPP IV and C-C chemokines,i.e. RANTES and the macrophage inflammatory proteins MIP-1α and MIP-1β, has been postulated during HIV-1 infection with macrophage-tropic (M-tropic) HIV-1 strains (17Oravecz T. Roderiquez G. Koffi J. Wang J. Ditto M. Bou-Habib D.C. Lusso P. Norcross M.A. Nat. Med. 1995; 1: 919-926Crossref PubMed Scopus (61) Google Scholar, 18Cocchi F. DeVico A.L. Garzino-Demo A. Arya S.K. Gallo R.C. Lusso P. Science. 1995; 270: 1811-1815Crossref PubMed Scopus (2620) Google Scholar). RANTES, MIP-1α, and MIP-1β inhibit HIV-1 infection by competing for the same seven transmembrane-spanning G protein-coupled C-C chemokine receptor 5 (CCR5) (19Murphy P.M. Cytokine Growth Factor Rev. 1996; 7: 47-64Crossref PubMed Scopus (281) Google Scholar, 20Premack B.A. Schall T.J. Nat. Med. 1996; 2: 1174-1178Crossref PubMed Scopus (572) Google Scholar, 21D'Souza M.P. Harden V.A. Nat. Med. 1996; 2: 1293-1300Crossref PubMed Scopus (271) Google Scholar). The observation that CD26/DPP IV reduces the chemotactic efficacy of RANTES while increasing its antiviral potency brings new insights into the mechanisms underlying the role of CD26/DPP IV during HIV-1 infection and inflammation. DISCUSSIONLimited NH2-terminal truncation of chemokines has different consequences for their biological potency resulting in either increased (C-X-C chemokines) or decreased (C-C chemokines) specific activity (4Walz A. Baggiolini M. Biochem. Biophys. Res. Commun. 1989; 159: 969-975Crossref PubMed Scopus (80) Google Scholar, 5Van Damme J. Rampart M. Conings R. Decock B. Van Osselaer N. Willems J. Billiau A. Eur. J. Immunol. 1990; 20: 2113-2118Crossref PubMed Scopus (80) Google Scholar, 6Clark-Lewis I. Schumacher C. Baggiolini M. Moser B. J. Biol. Chem. 1991; 266: 23128-23134Abstract Full Text PDF PubMed Google Scholar, 7Proost P. Wuyts A. Conings R. Lenaerts J.-P. Billiau A. Opdenakker G. Van Damme J. Biochemistry. 1993; 32: 10170-10177Crossref PubMed Scopus (71) Google Scholar, 8Gong J.-H. Uguccioni M. Dewald B. Baggiolini M. Clark-Lewis I. J. Biol. Chem. 1996; 271: 10521-10527Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, 9Gong J.H. Clark-Lewis I. J. Exp. Med. 1995; 181: 631-640Crossref PubMed Scopus (266) Google Scholar, 10Proudfoot A.E. Power C.A. Hoogewerf A.J. Montjovent M.O. Borlat F. Offord R.E. Wells T.N. J. Biol. Chem. 1996; 271: 2599-2603Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar). During the purification of GCP-2 and RANTES from natural sources, we detected significant quantities (more than 50% of the chemokine content) of NH2-terminally truncated variants missing the first two amino acids (Gly-Pro and Ser-Pro for GCP-2 and RANTES, respectively). We tested whether the exopeptidase CD26/DPP IV was able to process these and other chemokines with a penultimate Pro at their NH2 terminus and whether this cleavage resulted in an altered biological activity. Although the occurrence of the NH2-terminal Xaa-Pro motif as a target for CD26/DPP IV was observed several years ago, the failure of processing mature IL-1α, IL-1β, IL-2, and other cytokines by CD26/DPP IV indicated that peptides become less susceptible to cleavage by CD26/DPP IV with increasing length (11Fleischer B. Immunol. Today. 1994; 15: 180-184Abstract Full Text PDF PubMed Scopus (53) Google Scholar, 29Hoffmann T. Faust J. Neubert K. Ansorge S. FEBS Lett. 1993; 336: 61-64Crossref PubMed Scopus (115) Google Scholar). Indeed, the largest peptide (44 amino acids) reported to be sensitive to NH2-terminal truncation by CD26/DPP IV is growth hormone-releasing hormone (30Frohman L.A. Downs T. Heimer E. Felix A. J. Clin. Invest. 1989; 83: 1533-1540Crossref PubMed Scopus (161) Google Scholar).In this study, two chemokines of about 70 residues with Pro at the penultimate NH2-terminal position, i.e. the C-X-C chemokine GCP-2 and the C-C chemokine RANTES, were processed by CD26/DPP IV, but the C-C chemokines MCP-1, MCP-2, and MCP-3 were resistant to degradation by the enzyme. Earlier observations that naturally truncated froms of MCP-1, MCP-2, or MCP-3, missing two NH2-terminal amino acids, were not isolated from various cellular sources (22Proost P. Wuyts A. Conings R. Lenaerts J.-P. Put W. Van Damme J. Methods: Companion Methods in Enzymol. 1996; 10: 82-92Crossref Scopus (27) Google Scholar) confirm the specificity of CD26/DPP IV. Resistance of MCP-2 to CD26/DPP IV is a consequence of the presence of the NH2-terminal pyroglutamic acid, because recombinant MCP-2 with an NH2-terminal Gln was cleaved by CD26/DPP IV (data not shown). The importance of the NH2-terminal residues has been illustrated by chemical synthesis of truncated MCP-1 and MCP-3, which are devoid of monocyte chemotactic activity (8Gong J.-H. Uguccioni M. Dewald B. Baggiolini M. Clark-Lewis I. J. Biol. Chem. 1996; 271: 10521-10527Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, 9Gong J.H. Clark-Lewis I. J. Exp. Med. 1995; 181: 631-640Crossref PubMed Scopus (266) Google Scholar). Truncation of GCP-2 with CD26/DPP IV had no significant effect on the chemotactic and Ca2+-releasing capacity of the chemokine. In contrast, a 10–100-fold decreased monocyte chemotactic and intracellular Ca2+-releasing activity was detected with RANTES(3–68) processed by CD26/DPP IV. However, RANTES and RANTES(3–68) were reported to be equipotent eosinophil chemotactic proteins (31Noso N. Sticherling M. Bartels J. Mallet A.I. Christophers E. Schröder J.-M. J. Immunol. 1996; 156: 1946-1953PubMed Google Scholar). Expression of different RANTES receptors,i.e. CCR3 on eosinophils compared with CCR1 and CCR5 on mononuclear cells (3Taub D.D. Cytokine Growth Factor Rev. 1996; 7: 335-376Crossref Scopus (152) Google Scholar, 19Murphy P.M. Cytokine Growth Factor Rev. 1996; 7: 47-64Crossref PubMed Scopus (281) Google Scholar), may explain the different interaction of RANTES(3–68) with both cell types. In addition to monocytes, also memory type CD45RO+ T cells, which express CCR1, CCR5, and CD26, are important target cells for RANTES (32Wu B.L. Paxton W.A. Kassam N. Ruffing N. Rottman J.B. Sullivan N. Choe H. Sodroski J. Newman W. Koup R.A. MacKay C.R. J. Exp. Med. 1997; 185: 1681-1691Crossref PubMed Scopus (638) Google Scholar, 33Schall T.J. Bacon K. Toy K.J. Goeddel D.V. Nature. 1990; 347: 669-671Crossref PubMed Scopus (1255) Google Scholar). In view of these observations, a physical proximity between RANTES and CD26/DPP IV seems feasible, and therefore, the processing of RANTES by CD26/DPP IV is likely to be of biological significance.When tested as a RANTES inhibitor, 1 μg/ml of inactive RANTES(3–68) was able to inhibit monocyte chemotaxis toward 100 ng/ml and 300 ng/ml of intact RANTES. In Ca2+ mobilization experiments, 300 ng/ml of RANTES(3–68) only partially desensitized for a response toward intact RANTES. These results suggest that RANTES(3–68) binds to at least one receptor and that the interaction of RANTES(3–68) with the receptor(s) is sufficient for partial signal transduction (increase of the [Ca2+]i) but not for chemotaxis.Recently, chemokines, their receptors, and CD26/DPP IV have been linked to HIV-1-infection. Concerning the role of CD26/DPP IV in HIV-infection, contrasting reports have been published. A positive correlation between the level of CD26/DPP IV-expression and the susceptibility to infection with M-tropic HIV-1 viruses was found (17Oravecz T. Roderiquez G. Koffi J. Wang J. Ditto M. Bou-Habib D.C. Lusso P. Norcross M.A. Nat. Med. 1995; 1: 919-926Crossref PubMed Scopus (61) Google Scholar), whereas this correlation could not be detected for T-tropic viruses (34Morimoto C. Lord C.I. Zhang C. Duke-Cohan J.S. Letvin N.L. Schlossman S.F. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 9960-9964Crossref PubMed Scopus (73) Google Scholar). Moreover, CD26/DPP IV was described as a cofactor for HIV entry in CD4+ cells (35Callebaut C. Krust B. Jacotot E. Hovanessian A.G. Science. 1993; 262: 2045-2050Crossref PubMed Scopus (207) Google Scholar). In contrast, CD26/DPP IV+cells were found to be less susceptible to HIV infection than CD26/DPP IV− cells (34Morimoto C. Lord C.I. Zhang C. Duke-Cohan J.S. Letvin N.L. Schlossman S.F. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 9960-9964Crossref PubMed Scopus (73) Google Scholar). A specific decrease in CD26/DPP IV-expression was reported upon HIV-1 infection of cells with M-tropic, but not T-tropic viruses (17Oravecz T. Roderiquez G. Koffi J. Wang J. Ditto M. Bou-Habib D.C. Lusso P. Norcross M.A. Nat. Med. 1995; 1: 919-926Crossref PubMed Scopus (61) Google Scholar), and both the absolute number and the proportion of CD26+ T cells were decreased in HIV-infected persons (12Vanham G. Kestens L. De Meester I. Vingerhoets J. Penne G. Vanhoof G. Scharpé S. Heyligen H. Bosmans E. Ceuppens J.L. J. Acquired Immune Defic. Syndr. 1993; 6: 749-757PubMed Google Scholar).Several chemokines, including RANTES, were identified as inhibitors of HIV-1 infection (18Cocchi F. DeVico A.L. Garzino-Demo A. Arya S.K. Gallo R.C. Lusso P. Science. 1995; 270: 1811-1815Crossref PubMed Scopus (2620) Google Scholar). The use of CCR5 as a coreceptor by M-tropic viruses explains the inhibitory effect of the C-C chemokines RANTES, MIP-1α, and MIP-1β on HIV-1 infection (19Murphy P.M. Cytokine Growth Factor Rev. 1996; 7: 47-64Crossref PubMed Scopus (281) Google Scholar, 20Premack B.A. Schall T.J. Nat. Med. 1996; 2: 1174-1178Crossref PubMed Scopus (572) Google Scholar, 21D'Souza M.P. Harden V.A. Nat. Med. 1996; 2: 1293-1300Crossref PubMed Scopus (271) Google Scholar). Co-expression of CD26/DPP IV and CCR5 (32Wu B.L. Paxton W.A. Kassam N. Ruffing N. Rottman J.B. Sullivan N. Choe H. Sodroski J. Newman W. Koup R.A. MacKay C.R. J. Exp. Med. 1997; 185: 1681-1691Crossref PubMed Scopus (638) Google Scholar) could therefore explain the specific decrease of CD26+CD4+ cells during HIV infection. Recent reports on chemically synthesized RANTES(9–68), missing six extra NH2-terminal residues compared with RANTES(3–68), have shown a reduction of the anti-HIV activity of RANTES (36Arenzana-Seisdedos F. Virelizier J.-L. Rousset D. Clark-Lewis I. Loetscher P. Moser B. Baggiolini M. Nature. 1996; 383: 400Crossref PubMed Scopus (265) Google Scholar). RANTES(9–68) also functioned as a chemokine inhibitor, but about 10-fold higher amounts, compared with intact RANTES, were necessary to obtain a comparable anti-HIV-1 activity. NH2-terminally altered amino-oxypentane-RANTES also acts as a chemotaxis inhibitor and, in contrast to RANTES(9–68), was more efficient as an inhibitor of HIV-1 infection than intact RANTES (37Simmons G. Clapham P.R. Picard L. Offord R.E. Rosenkilde M.M. Schwartz T.W. Buser R. Wells T.N.C. Proudfoot A.E.I. Science. 1997; 276: 276-279Crossref PubMed Scopus (591) Google Scholar). Thus, minor modifications of RANTES at the NH2 terminus are detrimental to its chemotactic activity and alter its anti-HIV activity. Compared with intact RANTES, RANTES(3–68), generated by CD26/DPP IV cleavage, is a more efficient inhibitor of HIV-1 infection of peripheral blood mononuclear cells with M-tropic strains. At the same time, RANTES(3–68), which is a much weaker chemotaxis agonist compared with intact RANTES, can provide negative feedback to weaken the inflammatory response. Although it is at present impossible to discriminate between RANTES(1–68) and RANTES(3–68) in clinical samples, studies on the in vivo balance between both RANTES forms may provide interesting information on the (patho-)physiological role of RANTES(3–68).In conclusion, we have isolated naturally occurring forms of the chemokines GCP-2 and RANTES, missing their NH2-terminal Xaa-Pro motif. We demonstrated that CD26/DPP IV is able to cleave chemokines in vitro into these NH2-terminally truncated forms. Although truncated and intact GCP-2 are equally active, RANTES(3–68) becomes a natural chemotaxis inhibitor and is a more potent inhibitor of HIV-1-infection than intact RANTES. RANTES is the first cytokine reported, of which the biological activity can be modified by CD26/DPP IV. This finding may lead to novel insights on the role of this specific peptidase not only in HIV-infection but also in inflammatory processes and immune responses. Limited NH2-terminal truncation of chemokines has different consequences for their biological potency resulting in either increased (C-X-C chemokines) or decreased (C-C chemokines) specific activity (4Walz A. Baggiolini M. Biochem. Biophys. Res. Commun. 1989; 159: 969-975Crossref PubMed Scopus (80) Google Scholar, 5Van Damme J. Rampart M. Conings R. Decock B. Van Osselaer N. Willems J. Billiau A. Eur. J. Immunol. 1990; 20: 2113-2118Crossref PubMed Scopus (80) Google Scholar, 6Clark-Lewis I. Schumacher C. Baggiolini M. Moser B. J. Biol. Chem. 1991; 266: 23128-23134Abstract Full Text PDF PubMed Google Scholar, 7Proost P. Wuyts A. Conings R. Lenaerts J.-P. Billiau A. Opdenakker G. Van Damme J. Biochemistry. 1993; 32: 10170-10177Crossref PubMed Scopus (71) Google Scholar, 8Gong J.-H. Uguccioni M. Dewald B. Baggiolini M. Clark-Lewis I. J. Biol. Chem. 1996; 271: 10521-10527Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, 9Gong J.H. Clark-Lewis I. J. Exp. Med. 1995; 181: 631-640Crossref PubMed Scopus (266) Google Scholar, 10Proudfoot A.E. Power C.A. Hoogewerf A.J. Montjovent M.O. Borlat F. Offord R.E. Wells T.N. J. Biol. Chem. 1996; 271: 2599-2603Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar). During the purification of GCP-2 and RANTES from natural sources, we detected significant quantities (more than 50% of the chemokine content) of NH2-terminally truncated variants missing the first two amino acids (Gly-Pro and Ser-Pro for GCP-2 and RANTES, respectively). We tested whether the exopeptidase CD26/DPP IV was able to process these and other chemokines with a penultimate Pro at their NH2 terminus and whether this cleavage resulted in an altered biological activity. Although the occurrence of the NH2-terminal Xaa-Pro motif as a target for CD26/DPP IV was observed several years ago, the failure of processing mature IL-1α, IL-1β, IL-2, and other cytokines by CD26/DPP IV indicated that peptides become less susceptible to cleavage by CD26/DPP IV with increasing length (11Fleischer B. Immunol. Today. 1994; 15: 180-184Abstract Full Text PDF PubMed Scopus (53) Google Scholar, 29Hoffmann T. Faust J. Neubert K. Ansorge S. FEBS Lett. 1993; 336: 61-64Crossref PubMed Scopus (115) Google Scholar). Indeed, the largest peptide (44 amino acids) reported to be sensitive to NH2-terminal truncation by CD26/DPP IV is growth hormone-releasing hormone (30Frohman L.A. Downs T. Heimer E. Felix A. J. Clin. Invest. 1989; 83: 1533-1540Crossref PubMed Scopus (161) Google Scholar). In this study, two chemokines of about 70 residues with Pro at the penultimate NH2-terminal position, i.e. the C-X-C chemokine GCP-2 and the C-C chemokine RANTES, were processed by CD26/DPP IV, but the C-C chemokines MCP-1, MCP-2, and MCP-3 were resistant to degradation by the enzyme. Earlier observations that naturally truncated froms of MCP-1, MCP-2, or MCP-3, missing two NH2-terminal amino acids, were not isolated from various cellular sources (22Proost P. Wuyts A. Conings R. Lenaerts J.-P. Put W. Van Damme J. Methods: Companion Methods in Enzymol. 1996; 10: 82-92Crossref Scopus (27) Google Scholar) confirm the specificity of CD26/DPP IV. Resistance of MCP-2 to CD26/DPP IV is a consequence of the presence of the NH2-terminal pyroglutamic acid, because recombinant MCP-2 with an NH2-terminal Gln was cleaved by CD26/DPP IV (data not shown). The importance of the NH2-terminal residues has been illustrated by chemical synthesis of truncated MCP-1 and MCP-3, which are devoid of monocyte chemotactic activity (8Gong J.-H. Uguccioni M. Dewald B. Baggiolini M. Clark-Lewis I. J. Biol. Chem. 1996; 271: 10521-10527Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, 9Gong J.H. Clark-Lewis I. J. Exp. Med. 1995; 181: 631-640Crossref PubMed Scopus (266) Google Scholar). Truncation of GCP-2 with CD26/DPP IV had no significant effect on the chemotactic and Ca2+-releasing capacity of the chemokine. In contrast, a 10–100-fold decreased monocyte chemotactic and intracellular Ca2+-releasing activity was detected with RANTES(3–68) processed by CD26/DPP IV. However, RANTES and RANTES(3–68) were reported to be equipotent eosinophil chemotactic proteins (31Noso N. Sticherling M. Bartels J. Mallet A.I. Christophers E. Schröder J.-M. J. Immunol. 1996; 156: 1946-1953PubMed Google Scholar). Expression of different RANTES receptors,i.e. CCR3 on eosinophils compared with CCR1 and CCR5 on mononuclear cells (3Taub D.D. Cytokine Growth Factor Rev. 1996; 7: 335-376Crossref Scopus (152) Google Scholar, 19Murphy P.M. Cytokine Growth Factor Rev. 1996; 7: 47-64Crossref PubMed Scopus (281) Google Scholar), may explain the different interaction of RANTES(3–68) with both cell types. In addition to monocytes, also memory type CD45RO+ T cells, which express CCR1, CCR5, and CD26, are important target cells for RANTES (32Wu B.L. Paxton W.A. Kassam N. Ruffing N. Rottman J.B. Sullivan N. Choe H. Sodroski J. Newman W. Koup R.A. MacKay C.R. J. Exp. Med. 1997; 185: 1681-1691Crossref PubMed Scopus (638) Google Scholar, 33Schall T.J. Bacon K. Toy K.J. Goeddel D.V. Nature. 1990; 347: 669-671Crossref PubMed Scopus (1255) Google Scholar). In view of these observations, a physical proximity between RANTES and CD26/DPP IV seems feasible, and therefore, the processing of RANTES by CD26/DPP IV is likely to be of biological significance. When tested as a RANTES inhibitor, 1 μg/ml of inactive RANTES(3–68) was able to inhibit monocyte chemotaxis toward 100 ng/ml and 300 ng/ml of intact RANTES. In Ca2+ mobilization experiments, 300 ng/ml of RANTES(3–68) only partially desensitized for a response toward intact RANTES. These results suggest that RANTES(3–68) binds to at least one receptor and that the interaction of RANTES(3–68) with the receptor(s) is sufficient for partial signal transduction (increase of the [Ca2+]i) but not for chemotaxis. Recently, chemokines, their receptors, and CD26/DPP IV have been linked to HIV-1-infection. Concerning the role of CD26/DPP IV in HIV-infection, contrasting reports have been published. A positive correlation between the level of CD26/DPP IV-expression and the susceptibility to infection with M-tropic HIV-1 viruses was found (17Oravecz T. Roderiquez G. Koffi J. Wang J. Ditto M. Bou-Habib D.C. Lusso P. Norcross M.A. Nat. Med. 1995; 1: 919-926Crossref PubMed Scopus (61) Google Scholar), whereas this correlation could not be detected for T-tropic viruses (34Morimoto C. Lord C.I. Zhang C. Duke-Cohan J.S. Letvin N.L. Schlossman S.F. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 9960-9964Crossref PubMed Scopus (73) Google Scholar). Moreover, CD26/DPP IV was described as a cofactor for HIV entry in CD4+ cells (35Callebaut C. Krust B. Jacotot E. Hovanessian A.G. Science. 1993; 262: 2045-2050Crossref PubMed Scopus (207) Google Scholar). In contrast, CD26/DPP IV+cells were found to be less susceptible to HIV infection than CD26/DPP IV− cells (34Morimoto C. Lord C.I. Zhang C. Duke-Cohan J.S. Letvin N.L. Schlossman S.F. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 9960-9964Crossref PubMed Scopus (73) Google Scholar). A specific decrease in CD26/DPP IV-expression was reported upon HIV-1 infection of cells with M-tropic, but not T-tropic viruses (17Oravecz T. Roderiquez G. Koffi J. Wang J. Ditto M. Bou-Habib D.C. Lusso P. Norcross M.A. Nat. Med. 1995; 1: 919-926Crossref PubMed Scopus (61) Google Scholar), and both the absolute number and the proportion of CD26+ T cells were decreased in HIV-infected persons (12Vanham G. Kestens L. De Meester I. Vingerhoets J. Penne G. Vanhoof G. Scharpé S. Heyligen H. Bosmans E. Ceuppens J.L. J. Acquired Immune Defic. Syndr. 1993; 6: 749-757PubMed Google Scholar). Several chemokines, including RANTES, were identified as inhibitors of HIV-1 infection (18Cocchi F. DeVico A.L. Garzino-Demo A. Arya S.K. Gallo R.C. Lusso P. Science. 1995; 270: 1811-1815Crossref PubMed Scopus (2620) Google Scholar). The use of CCR5 as a coreceptor by M-tropic viruses explains the inhibitory effect of the C-C chemokines RANTES, MIP-1α, and MIP-1β on HIV-1 infection (19Murphy P.M. Cytokine Growth Factor Rev. 1996; 7: 47-64Crossref PubMed Scopus (281) Google Scholar, 20Premack B.A. Schall T.J. Nat. Med. 1996; 2: 1174-1178Crossref PubMed Scopus (572) Google Scholar, 21D'Souza M.P. Harden V.A. Nat. Med. 1996; 2: 1293-1300Crossref PubMed Scopus (271) Google Scholar). Co-expression of CD26/DPP IV and CCR5 (32Wu B.L. Paxton W.A. Kassam N. Ruffing N. Rottman J.B. Sullivan N. Choe H. Sodroski J. Newman W. Koup R.A. MacKay C.R. J. Exp. Med. 1997; 185: 1681-1691Crossref PubMed Scopus (638) Google Scholar) could therefore explain the specific decrease of CD26+CD4+ cells during HIV infection. Recent reports on chemically synthesized RANTES(9–68), missing six extra NH2-terminal residues compared with RANTES(3–68), have shown a reduction of the anti-HIV activity of RANTES (36Arenzana-Seisdedos F. Virelizier J.-L. Rousset D. Clark-Lewis I. Loetscher P. Moser B. Baggiolini M. Nature. 1996; 383: 400Crossref PubMed Scopus (265) Google Scholar). RANTES(9–68) also functioned as a chemokine inhibitor, but about 10-fold higher amounts, compared with intact RANTES, were necessary to obtain a comparable anti-HIV-1 activity. NH2-terminally altered amino-oxypentane-RANTES also acts as a chemotaxis inhibitor and, in contrast to RANTES(9–68), was more efficient as an inhibitor of HIV-1 infection than intact RANTES (37Simmons G. Clapham P.R. Picard L. Offord R.E. Rosenkilde M.M. Schwartz T.W. Buser R. Wells T.N.C. Proudfoot A.E.I. Science. 1997; 276: 276-279Crossref PubMed Scopus (591) Google Scholar). Thus, minor modifications of RANTES at the NH2 terminus are detrimental to its chemotactic activity and alter its anti-HIV activity. Compared with intact RANTES, RANTES(3–68), generated by CD26/DPP IV cleavage, is a more efficient inhibitor of HIV-1 infection of peripheral blood mononuclear cells with M-tropic strains. At the same time, RANTES(3–68), which is a much weaker chemotaxis agonist compared with intact RANTES, can provide negative feedback to weaken the inflammatory response. Although it is at present impossible to discriminate between RANTES(1–68) and RANTES(3–68) in clinical samples, studies on the in vivo balance between both RANTES forms may provide interesting information on the (patho-)physiological role of RANTES(3–68). In conclusion, we have isolated naturally occurring forms of the chemokines GCP-2 and RANTES, missing their NH2-terminal Xaa-Pro motif. We demonstrated that CD26/DPP IV is able to cleave chemokines in vitro into these NH2-terminally truncated forms. Although truncated and intact GCP-2 are equally active, RANTES(3–68) becomes a natural chemotaxis inhibitor and is a more potent inhibitor of HIV-1-infection than intact RANTES. RANTES is the first cytokine reported, of which the biological activity can be modified by CD26/DPP IV. This finding may lead to novel insights on the role of this specific peptidase not only in HIV-infection but also in inflammatory processes and immune responses. We thank Sandra Claes, René Conings, Erik Fonteyn, Jean-Pierre Lenaerts, and Willy Put for technical assistance." @default.
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W2005991858 date "1998-03-01" @default.
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W2005991858 title "Amino-terminal Truncation of Chemokines by CD26/Dipeptidyl-peptidase IV" @default.
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