In vivo and in vitro roles of IL-21 in inflammation.
IL-21 is a cytokine known to mediate its biological action via the IL-21R, composed of a specific chain, IL-21Ralpha, and the common gamma-chain (CD132). Recent data suggest that IL-21 possesses proinflammatory properties. However, there is no clear evidence that IL-21 induces inflammation in vivo and, curiously, the interaction between IL-21 and neutrophils has never been investigated, despite the fact that these cells express CD132 and respond to other CD132-dependent cytokines involved in inflammatory disorders. Using the murine air pouch model, we found that IL-21 induced inflammation in vivo, based on recruitment of neutrophil and monocyte populations. In contrast to LPS, administration of IL-21 into the air pouch did not significantly increase the concentration of IL-6, CCL5, CCL3, and CXCL2. We demonstrated that HL-60 cells expressed IL-21Ralpha, which is down-regulated during their differentiation toward neutrophils, and that IL-21Ralpha is not detected in neutrophils. Concomitant with this, IL-21 induced Erk-1/2 phosphorylation in HL-60 cells, but not in neutrophils. To eliminate the possibility that IL-21 could activate neutrophils even in the absence of IL-21Ralpha, we demonstrated that IL-21 did not modulate several neutrophil functions. IL-21-induced Erk-1/2 phosphorylation was not associated with proliferation or differentiation of HL-60 toward neutrophils, monocytes, or macrophages. IL-21Ralpha was detected in human monocytes and monocyte-derived macrophages, but IL-21 increased CXCL8 production only in monocyte-derived macrophages. We conclude that IL-21 is a proinflammatory cytokine, but not a neutrophil agonist. We propose that IL-21 attracts neutrophils indirectly in vivo via a mechanism independent of IL-6, CCL3, CCL5, and CXCL2 production.
Pelletier
Martin
M
Institut National de la Recherche Scientifique (INRS)-Institut Armand-Frappier, Université du Québec, Pointe-Claire, Canada.
Bouchard
Amélie
A
Girard
Denis
D
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D054418:Chemokine CCL20; D018946:Chemokine CCL5; D054360:Chemokine CXCL1; D019742:Chemokines, CC / Q000096:biosynthesis; D019743:Chemokines, CXC / Q000096:biosynthesis; D006133:Growth Substances / Q000502:physiology; D018922:HL-60 Cells; D006801:Humans; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000008:administration & dosage* / Q000819:agonists / Q000502:physiology*; D007279:Injections, Subcutaneous; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D053738:Interleukin-21 Receptor alpha Subunit; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D007378:Interleukins / Q000008:administration & dosage* / Q000819:agonists / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000276:immunology; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D053655:Receptors, Interleukin-21; D000098546:Interleukin-21
C108355:CCL20 protein, human; C483024:CCL5 protein, human; C475829:CXCL1 protein, human; D054418:Chemokine CCL20; D018946:Chemokine CCL5; D054360:Chemokine CXCL1; D019742:Chemokines, CC; D019743:Chemokines, CXC; D006133:Growth Substances; C508117:IL21R protein, human; C508118:Il21r protein, mouse; D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins; D053738:Interleukin-21 Receptor alpha Subunit; D015850:Interleukin-6; D016209:Interleukin-8; D007378:Interleukins; D019402:Macrophage Inflammatory Proteins; D021122:Protein Subunits; D018123:Receptors, Interleukin; D053655:Receptors, Interleukin-21; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000098546:Interleukin-21