The Journal of Experimental Medicine
Janeway's Immunobiology 7th Edition
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© The Rockefeller University Press, 0022-1007/1999/10/1175/ $5.00
The Journal of Experimental Medicine, Volume 190, Number 8, October 18, 1999 1175-1182

CD47 Ligation Selectively Downregulates Human Interleukin 12 Production

Myriam Armanta, Marie-Noëlle Avicea, Patrice Hermanna, Manuel Rubioa, Mamoru Kiniwaa, Guy Delespessea, and Marika Sarfatia
a Laboratoire Allergie, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CHUM), Campus Notre-Dame, Quebec H2L 4M1, Canada

Correspondence to: Marika Sarfati, University of Montreal, Laboratoire Allergie (M4211-K), Centre de Recherche du CHUM, Campus Notre-Dame, 1560 Sherbrooke Street East, Montreal, Quebec H2L 4M1, Canada. Tel:514-281-6000 ext. 6632 Fax:514-896-4753 E-mail:sarfatm{at}poste.umontreal.ca.

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)-ß and IL-10 production, and the suppressive effect on IL-12 was not due to autocrine secretion of TGF-ß or IL-10. The IL-12 inhibition was not mediated by Fc{gamma} receptor ligation, did not require extracellular Ca2+ 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.

Key Words: CD47, interleukin 12, monocytes, thrombospondin


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