CD47 ligation selectively downregulates human interleukin 12 production.
Interleukin (IL)-12 plays a key role not only in protective innate and adaptive T helper cell type 1 (Th1) responses but also in chronic inflammatory diseases. We report here that engagement of CD47 by either monoclonal antibody, its natural ligand thrombospondin (TSP), or 4N1K (a peptide of the COOH-terminal domain of TSP selectively binding CD47) inhibits IL-12 release by monocytes. The suppression occurred after T cell-dependent or -independent stimulation of monocytes and was selective for IL-12 inasmuch as the production of tumor necrosis factor (TNF)-alpha, IL-1, IL-6, and granulocyte/macrophage colony-stimulating factor was not inhibited. CD47 ligation did not alter transforming growth factor (TGF)-beta and IL-10 production, and the suppressive effect on IL-12 was not due to autocrine secretion of TGF-beta or IL-10. The IL-12 inhibition was not mediated by Fcgamma receptor ligation, did not require extracellular Ca(2+) influx, but was reversed by two phosphoinositide 3-kinase inhibitors (wortmannin and Ly294002). Thus, engagement of CD47 on monocytes by TSP, which transiently accumulates at the inflammatory site, is a novel and unexplored pathway to selectively downregulate IL-12 response. The pathway may be relevant in limiting the duration and intensity of the inflammatory response, and in developing novel therapeutic strategies for Th1-mediated diseases.
Armant
M
M
Laboratoire Allergie, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CHUM), Campus Notre-Dame, Quebec H2L 4M1, Canada.
Avice
M N
MN
Hermann
P
P
Rubio
M
M
Kiniwa
M
M
Delespesse
G
G
Sarfati
M
M
D000730:Androstadienes / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism; D015703:Antigens, CD / Q000276:immunology*; D051928:CD47 Antigen; D002352:Carrier Proteins / Q000276:immunology*; D002867:Chromones / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D018664:Interleukin-12 / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology; D009025:Morpholines / Q000494:pharmacology; D009842:Oligopeptides / Q000276:immunology / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011485:Protein Binding / Q000276:immunology; D013601:T-Lymphocytes / Q000378:metabolism; D019699:Thrombospondins / Q000276:immunology / Q000494:pharmacology; D000077191:Wortmannin
C120273:4N1K peptide; D000730:Androstadienes; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D051928:CD47 Antigen; C497894:CD47 protein, human; D002352:Carrier Proteins; D002867:Chromones; D016207:Cytokines; D004791:Enzyme Inhibitors; D007140:Immunoglobulin Fab Fragments; D009025:Morpholines; D009842:Oligopeptides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019699:Thrombospondins; D018664:Interleukin-12; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D000077191:Wortmannin