Enhanced anti-HIV-1 activity and altered chemotactic potency of NH2-terminally processed macrophage-derived chemokine (MDC) imply an additional MDC receptor.
Posttranslational processing of chemokines increases (IL-8) or decreases (monocyte chemotactic protein-1) their chemotactic potency. Macrophage-derived chemokine (MDC) attracts monocytes, dendritic cells, activated lymphocytes, and NK cells and has reportedly anti-HIV-1 activity. Here we report that truncation of MDC by deletion of two NH2-terminal residues resulted in impaired binding to CC chemokine receptor (CCR)4, the only identified MDC receptor so far. Truncated MDC(3-69) failed to desensitize calcium mobilization by MDC(1-69) or thymus- and activation-regulated chemokine (TARC), another CCR4 ligand. MDC(3-69) lacked HUT-78 T cell chemotactic activity but retained its capacity to attract monocytes and to desensitize chemotaxis. Compared with MDC(1-69), MDC(3-69) had weak but enhanced antiviral activity against M- and T-tropic HIV-1 strains. Furthermore, both MDC forms failed to signal through the orphan receptors Bonzo/STRL33 and BOB/GPR15 and to desensitize RANTES and stromal cell-derived factor (SDF)-1 responses in CCR5-transfected and CXC chemokine receptor (CXCR)4-transfected cells, respectively. These findings suggest that MDC recognizes another, yet unidentified, receptor. We conclude that minimal NH2-terminal truncation of MDC differentially affects its various immunologic functions.
Struyf
S
S
Laboratory of Molecular Immunology, Rega Institute for Medical Research, University of Leuven, Belgium.
Proost
P
P
Sozzani
S
S
Mantovani
A
A
Wuyts
A
A
De Clercq
E
E
Schols
D
D
Van Damme
J
J
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D054422:Chemokine CCL22; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects* / Q000276:immunology; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D009000:Monocytes / Q000276:immunology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D054398:Receptors, CCR4; D019707:Receptors, Chemokine / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D019380:Anti-HIV Agents; C515482:CCL22 protein, human; C515354:CCR4 protein, human; C515483:Ccl22 protein, mouse; C515355:Ccr4 protein, mouse; D054422:Chemokine CCL22; D019742:Chemokines, CC; D010446:Peptide Fragments; D054398:Receptors, CCR4; D019707:Receptors, Chemokine; D011994:Recombinant Proteins