Amino-terminal truncation of chemokines by CD26/dipeptidyl-peptidase IV. Conversion of RANTES into a potent inhibitor of monocyte chemotaxis and HIV-1-infection.
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.
Proost
P
P
Laboratory of Molecular Immunology, Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium. Paul.Proost@rega.kuleuven.ac.be
De Meester
I
I
Schols
D
D
Struyf
S
S
Lambeir
A M
AM
Wuyts
A
A
Opdenakker
G
G
De Clercq
E
E
Scharpé
S
S
Van Damme
J
J
D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D018946:Chemokine CCL5 / Q000737:chemistry / Q000378:metabolism*; D054427:Chemokine CXCL6; D019743:Chemokines, CXC / Q000737:chemistry / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1; D006801:Humans; D007113:Immunity, Innate; D009504:Neutrophils / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
C515503:CXCL6 protein, human; D018946:Chemokine CCL5; D054427:Chemokine CXCL6; D019743:Chemokines, CXC; D010446:Peptide Fragments; D019713:Receptors, CCR5; D018819:Dipeptidyl Peptidase 4; D002118:Calcium