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CD47 ligation selectively downregulates human interleukin 12 production.

Armant M, Avice MN, Hermann P, Rubio M, Kiniwa M, Delespesse G, Sarfati M - J. Exp. Med. (1999)

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire Allergie, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CHUM), Campus Notre-Dame, Quebec H2L 4M1, Canada.

ABSTRACT
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.

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PI 3-K inhibitors restore IL-12 production. Monocytes (106/ml) were stimulated with SAC and IFN-γ in the absence or presence of CD47 mAb (10 μg/ml) and titrated concentrations of wortmannin or Ly294002. IL-12p70 release was measured after 20 h. Results represent mean values from one of three independent experiments using three different donors.
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Figure 4: PI 3-K inhibitors restore IL-12 production. Monocytes (106/ml) were stimulated with SAC and IFN-γ in the absence or presence of CD47 mAb (10 μg/ml) and titrated concentrations of wortmannin or Ly294002. IL-12p70 release was measured after 20 h. Results represent mean values from one of three independent experiments using three different donors.

Mentions: Since TSP signaling of focal adhesion in endothelial cells requires activation of phosphoinositide 3-kinase (PI 3-K [20]), we explored the involvement of this pathway in CD47 mAb–mediated suppression of IL-12 release by using two PI 3-K inhibitors, wortmannin and Ly294002. We found that both PI 3-K inhibitors restored IL-12 release in a dose-dependent manner (Fig. 4) with no effect on TNF-α secretion (data not shown). However, neither protein kinase C (e.g., H7, HA1004) nor protein tyrosine kinase inhibitors (e.g., herbimycin) prevented CD47 mAb–mediated inhibition of IL-12 release (not shown). Taken collectively, our results suggest that engagement of CD47 on monocytes by mAb, its natural ligand TSP, and 4N1K peptide specifically suppressed IL-12 secretion through an Fc and Ca2+–independent but PI 3-K–dependent pathway.


CD47 ligation selectively downregulates human interleukin 12 production.

Armant M, Avice MN, Hermann P, Rubio M, Kiniwa M, Delespesse G, Sarfati M - J. Exp. Med. (1999)

PI 3-K inhibitors restore IL-12 production. Monocytes (106/ml) were stimulated with SAC and IFN-γ in the absence or presence of CD47 mAb (10 μg/ml) and titrated concentrations of wortmannin or Ly294002. IL-12p70 release was measured after 20 h. Results represent mean values from one of three independent experiments using three different donors.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195669&req=5

Figure 4: PI 3-K inhibitors restore IL-12 production. Monocytes (106/ml) were stimulated with SAC and IFN-γ in the absence or presence of CD47 mAb (10 μg/ml) and titrated concentrations of wortmannin or Ly294002. IL-12p70 release was measured after 20 h. Results represent mean values from one of three independent experiments using three different donors.
Mentions: Since TSP signaling of focal adhesion in endothelial cells requires activation of phosphoinositide 3-kinase (PI 3-K [20]), we explored the involvement of this pathway in CD47 mAb–mediated suppression of IL-12 release by using two PI 3-K inhibitors, wortmannin and Ly294002. We found that both PI 3-K inhibitors restored IL-12 release in a dose-dependent manner (Fig. 4) with no effect on TNF-α secretion (data not shown). However, neither protein kinase C (e.g., H7, HA1004) nor protein tyrosine kinase inhibitors (e.g., herbimycin) prevented CD47 mAb–mediated inhibition of IL-12 release (not shown). Taken collectively, our results suggest that engagement of CD47 on monocytes by mAb, its natural ligand TSP, and 4N1K peptide specifically suppressed IL-12 secretion through an Fc and Ca2+–independent but PI 3-K–dependent pathway.

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire Allergie, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CHUM), Campus Notre-Dame, Quebec H2L 4M1, Canada.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus