Anaphylatoxin C5a induces monocyte recruitment and differentiation into dendritic cells by TNF-alpha and prostaglandin E2-dependent mechanisms.
Although monocytes can be directed to develop into dendritic cells (DC) in vitro, the molecular mechanisms that induce their transformation in vivo are largely unknown. In the present study we employed an in vivo SCID mouse model to investigate the impact of two proinflammatory chemotaxins, the anaphylatoxin C5a and the chemokine macrophage inflammatory protein-1alpha (CCL3), on the differentiation of human monocytes and immature DC generated from monocytes in the presence of GM-CSF and IL-4. Both C5a and macrophage inflammatory protein-1alpha recruited human monocytes and immature DC into the peritoneal cavity of SCID mice, but only C5a induced their differentiation into phenotypically mature DC by 48 h after injection. Macrophages derived from monocytes by in vitro culture were resistant to C5a-mediated transformation in vivo. The effect of C5a was indirect, since C5a-stimulated TNF-alpha and PGE(2) were found to be obligatory as well as sufficient to induce differentiation of monocytes. In contrast to monocytes, in vitro generated immature DC required TNF-alpha, but not PGE(2), for their C5a-mediated maturation in vivo. C5a-transformed monocytes represented an inflammatory type of DC, as they constitutively secreted high amounts of TNF-alpha, but also retained the capacity to release the Th1 cytokine IL-12 p70 upon stimulation with CD40 ligand. In summary, we identified for the first time a cascade of inflammatory signals that can induce the transformation of monocytes into DC in vivo. This novel function emphasizes the important immunoregulatory role of C5a at the interface of innate and adaptive immunity.
Soruri
Afsaneh
A
Department of Immunology, Georg August University-Gottingen, Kreuzbergring 57, D-37075 Gottingen, Germany.
Riggert
Joachim
J
Schlott
Thilo
T
Kiafard
Ziba
Z
Dettmer
Claudia
C
Zwirner
Jörg
J
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000276:immunology*; D015936:Complement C5a / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000502:physiology*; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D006801:Humans; D007106:Immune Sera / Q000008:administration & dosage; D007213:Indomethacin / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D018664:Interleukin-12 / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008863:Microspheres; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology; D011448:Prostaglandin Antagonists / Q000008:administration & dosage; D011453:Prostaglandins / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism / Q000502:physiology*
D007106:Immune Sera; D011448:Prostaglandin Antagonists; D011453:Prostaglandins; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D015936:Complement C5a; D015232:Dinoprostone; D007213:Indomethacin