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The vitronectin receptor and its associated CD47 molecule mediates proinflammatory cytokine synthesis in human monocytes by interaction with soluble CD23.

Hermann P, Armant M, Brown E, Rubio M, Ishihara H, Ulrich D, Caspary RG, Lindberg FP, Armitage R, Maliszewski C, Delespesse G, Sarfati M - J. Cell Biol. (1999)

Bottom Line: Surprisingly, anti-CD47 and beta3 mAbs do not block sCD23 binding to alphav+beta3+ T cell lines, whereas Vn and an alphav mAb (clone AMF7) do inhibit sCD23 binding, suggesting the VnR complex may be a functional receptor for sCD23. sCD23 directly binds alphav+beta3+/CD47(-) cell lines, but coexpression of CD47 increases binding.Moreover, sCD23 binds purified alphav protein and a single human alphav chain CHO transfectant.We conclude that the VnR and its associated CD47 molecule may function as a novel receptor for sCD23 to mediate its proinflammatory activity and, as such, may be involved in the inflammatory process of the immune response.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire Allergie, Centre de recherch¿e Louis-Charles Simard, Pavillon Notre-Dame, Centre Hospitalier Université de Montréal (CHUM), Montreal, Quebec H2L 4M1, Canada.

ABSTRACT
The vitronectin receptor, alphavbeta3 integrin, plays an important role in tumor cell invasion, angiogenesis, and phagocytosis of apoptotic cells. CD47, a member of the multispan transmembrane receptor family, physically and functionally associates with vitronectin receptor (VnR). Although vitronectin (Vn) is not a ligand of CD47, anti-CD47 and beta3 mAbs suppress Vn, but not fibronectin (Fn) binding and function. Here, we show that anti-CD47, anti-beta3 mAb and Vn, but not Fn, inhibit sCD23-mediated proinflammatory function (TNF-alpha, IL-12, and IFN-gamma release). Surprisingly, anti-CD47 and beta3 mAbs do not block sCD23 binding to alphav+beta3+ T cell lines, whereas Vn and an alphav mAb (clone AMF7) do inhibit sCD23 binding, suggesting the VnR complex may be a functional receptor for sCD23. sCD23 directly binds alphav+beta3+/CD47(-) cell lines, but coexpression of CD47 increases binding. Moreover, sCD23 binds purified alphav protein and a single human alphav chain CHO transfectant. We conclude that the VnR and its associated CD47 molecule may function as a novel receptor for sCD23 to mediate its proinflammatory activity and, as such, may be involved in the inflammatory process of the immune response.

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Effect of mAbs or natural ligands to VnR/CD47 complex on sCD23 binding to Jurkat and Raji cell lines. Jurkat  αv+β3+ (CD51+/CD61+) (a–e), or Raji αv+β3− (CD51+/CD61−)  (f) cell lines were stained by B-BSA (dotted line) or B-sCD23 in  the absence (solid line) or presence of the following inhibitors  (plain histograms): anti-CD23 mAb (a); anti-CD47 mAbs (cocktail of four anti-CD47 mAbs; b); anti-β3 (CD61) mAb (c); Vn (d);  anti-αv (CD51) mAb (e and f). B-sCD23 plus isotype-matched  control mAb (a–c, e, and f) or Fn (d) were shown as dashed lines.  One representative experiment out of four.
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Figure 5: Effect of mAbs or natural ligands to VnR/CD47 complex on sCD23 binding to Jurkat and Raji cell lines. Jurkat αv+β3+ (CD51+/CD61+) (a–e), or Raji αv+β3− (CD51+/CD61−) (f) cell lines were stained by B-BSA (dotted line) or B-sCD23 in the absence (solid line) or presence of the following inhibitors (plain histograms): anti-CD23 mAb (a); anti-CD47 mAbs (cocktail of four anti-CD47 mAbs; b); anti-β3 (CD61) mAb (c); Vn (d); anti-αv (CD51) mAb (e and f). B-sCD23 plus isotype-matched control mAb (a–c, e, and f) or Fn (d) were shown as dashed lines. One representative experiment out of four.

Mentions: We next investigated the ability of mAbs directed to the VnR complex, anti-CD47, CD61 (β3) and αvβ3 (LM609) mAbs, and natural ligands of VnR, Vn, Fn, and RGDS peptides, to alter sCD23 binding to the Jurkat T cell line. Unexpectedly, anti-CD47 mAbs, alone or in combination (Fig. 5 b), anti-CD61 (Fig. 5 c), or anti-αvβ3 clone LM609 (not shown) did not inhibit sCD23 binding to Jurkat or monocytes (Hermann, P., unpublished observations). Note that sCD23 binding was specifically suppressed by anti-CD23 mAb (Fig. 5 a). The data suggested ligation of the CD47 or β3 chain of the trimolecular complex by mAbs could indirectly inhibit sCD23 function by providing a negative signal to the target cells, or by modifying CD47 complex configuration without displacing the sCD23 molecule. We examined whether engagement of VnR/CD47 complex by its natural ligands would modify sCD23 binding. As shown in Fig. 5 d, Vn, but not Fn or RGDS peptide (not shown), significantly inhibited sCD23 binding, strongly suggesting the VnR complex was involved in the secretion of proinflammatory cytokine via interaction with sCD23.


The vitronectin receptor and its associated CD47 molecule mediates proinflammatory cytokine synthesis in human monocytes by interaction with soluble CD23.

Hermann P, Armant M, Brown E, Rubio M, Ishihara H, Ulrich D, Caspary RG, Lindberg FP, Armitage R, Maliszewski C, Delespesse G, Sarfati M - J. Cell Biol. (1999)

Effect of mAbs or natural ligands to VnR/CD47 complex on sCD23 binding to Jurkat and Raji cell lines. Jurkat  αv+β3+ (CD51+/CD61+) (a–e), or Raji αv+β3− (CD51+/CD61−)  (f) cell lines were stained by B-BSA (dotted line) or B-sCD23 in  the absence (solid line) or presence of the following inhibitors  (plain histograms): anti-CD23 mAb (a); anti-CD47 mAbs (cocktail of four anti-CD47 mAbs; b); anti-β3 (CD61) mAb (c); Vn (d);  anti-αv (CD51) mAb (e and f). B-sCD23 plus isotype-matched  control mAb (a–c, e, and f) or Fn (d) were shown as dashed lines.  One representative experiment out of four.
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Related In: Results  -  Collection

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Figure 5: Effect of mAbs or natural ligands to VnR/CD47 complex on sCD23 binding to Jurkat and Raji cell lines. Jurkat αv+β3+ (CD51+/CD61+) (a–e), or Raji αv+β3− (CD51+/CD61−) (f) cell lines were stained by B-BSA (dotted line) or B-sCD23 in the absence (solid line) or presence of the following inhibitors (plain histograms): anti-CD23 mAb (a); anti-CD47 mAbs (cocktail of four anti-CD47 mAbs; b); anti-β3 (CD61) mAb (c); Vn (d); anti-αv (CD51) mAb (e and f). B-sCD23 plus isotype-matched control mAb (a–c, e, and f) or Fn (d) were shown as dashed lines. One representative experiment out of four.
Mentions: We next investigated the ability of mAbs directed to the VnR complex, anti-CD47, CD61 (β3) and αvβ3 (LM609) mAbs, and natural ligands of VnR, Vn, Fn, and RGDS peptides, to alter sCD23 binding to the Jurkat T cell line. Unexpectedly, anti-CD47 mAbs, alone or in combination (Fig. 5 b), anti-CD61 (Fig. 5 c), or anti-αvβ3 clone LM609 (not shown) did not inhibit sCD23 binding to Jurkat or monocytes (Hermann, P., unpublished observations). Note that sCD23 binding was specifically suppressed by anti-CD23 mAb (Fig. 5 a). The data suggested ligation of the CD47 or β3 chain of the trimolecular complex by mAbs could indirectly inhibit sCD23 function by providing a negative signal to the target cells, or by modifying CD47 complex configuration without displacing the sCD23 molecule. We examined whether engagement of VnR/CD47 complex by its natural ligands would modify sCD23 binding. As shown in Fig. 5 d, Vn, but not Fn or RGDS peptide (not shown), significantly inhibited sCD23 binding, strongly suggesting the VnR complex was involved in the secretion of proinflammatory cytokine via interaction with sCD23.

Bottom Line: Surprisingly, anti-CD47 and beta3 mAbs do not block sCD23 binding to alphav+beta3+ T cell lines, whereas Vn and an alphav mAb (clone AMF7) do inhibit sCD23 binding, suggesting the VnR complex may be a functional receptor for sCD23. sCD23 directly binds alphav+beta3+/CD47(-) cell lines, but coexpression of CD47 increases binding.Moreover, sCD23 binds purified alphav protein and a single human alphav chain CHO transfectant.We conclude that the VnR and its associated CD47 molecule may function as a novel receptor for sCD23 to mediate its proinflammatory activity and, as such, may be involved in the inflammatory process of the immune response.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire Allergie, Centre de recherch¿e Louis-Charles Simard, Pavillon Notre-Dame, Centre Hospitalier Université de Montréal (CHUM), Montreal, Quebec H2L 4M1, Canada.

ABSTRACT
The vitronectin receptor, alphavbeta3 integrin, plays an important role in tumor cell invasion, angiogenesis, and phagocytosis of apoptotic cells. CD47, a member of the multispan transmembrane receptor family, physically and functionally associates with vitronectin receptor (VnR). Although vitronectin (Vn) is not a ligand of CD47, anti-CD47 and beta3 mAbs suppress Vn, but not fibronectin (Fn) binding and function. Here, we show that anti-CD47, anti-beta3 mAb and Vn, but not Fn, inhibit sCD23-mediated proinflammatory function (TNF-alpha, IL-12, and IFN-gamma release). Surprisingly, anti-CD47 and beta3 mAbs do not block sCD23 binding to alphav+beta3+ T cell lines, whereas Vn and an alphav mAb (clone AMF7) do inhibit sCD23 binding, suggesting the VnR complex may be a functional receptor for sCD23. sCD23 directly binds alphav+beta3+/CD47(-) cell lines, but coexpression of CD47 increases binding. Moreover, sCD23 binds purified alphav protein and a single human alphav chain CHO transfectant. We conclude that the VnR and its associated CD47 molecule may function as a novel receptor for sCD23 to mediate its proinflammatory activity and, as such, may be involved in the inflammatory process of the immune response.

Show MeSH
Related in: MedlinePlus