IL-9 inhibits oxidative burst and TNF-alpha release in lipopolysaccharide-stimulated human monocytes through TGF-beta.
IL-9 is a Th2 cytokine that exerts pleiotropic activities on T cells, B cells, mast cells, hematopoietic progenitors, and lung epithelial cells, but no effect of this cytokine has been reported so far on mononuclear phagocytes. Human blood monocytes preincubated with IL-9 for 24 h before LPS or PMA stimulation exhibited a decreased oxidative burst, even in the presence of IFN-gamma. The inhibitory effect of IL-9 was specifically abolished by anti-hIL-9R mAb, and the presence of IL-9 receptors was demonstrated on human blood monocytes by FACS. IL-9 also down-regulated TNF-alpha and IL-10 release by LPS-stimulated monocytes. In addition, IL-9 strongly up-regulated the production of TGF-beta1 by LPS-stimulated monocytes. The suppressive effect of IL-9 on the respiratory burst and TNF-alpha production in LPS-stimulated monocytes was significantly inhibited by anti-TGF-beta1, but not by anti-IL-10Rbeta mAb. Furthermore, IL-9 inhibited LPS-induced activation of extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases in monocytes through a TGF-beta-mediated induction of protein phosphatase activity. In contrast, IL-4, which exerts a similar inhibitory effect on the oxidative burst and TNF-alpha release by monocytes, acts primarily through a down-regulation of LPS receptors. Thus, IL-9 deactivates LPS-stimulated blood mononuclear phagocytes, and the mechanism of inhibition involves the potentiation of TGF-beta1 production and extracellular signal-regulated kinase inhibition. These findings highlight a new target cell for IL-9 and may account for the beneficial activity of IL-9 in animal models of exaggerated inflammatory response.
Pilette
Charles
C
Experimental Medicine Unit and Ludwig Institute for Cancer Research, Christian de Duve Institute of Cellular Pathology, and Laboratory of Hematology, Université de Louvain, Brussels, Belgium. charles.pilette@mexp.acl.ac.be
Ouadrhiri
Youssef
Y
Van Snick
Jacques
J
Renauld
Jean-Christophe
JC
Staquet
Philippe
P
Vaerman
Jean-Pierre
JP
Sibille
Yves
Y
D000276:Adjuvants, Immunologic / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology; D004338:Drug Combinations; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000378:metabolism; D016906:Interleukin-9 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D008262:Macrophage Activation / Q000276:immunology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009000:Monocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000276:immunology; D053651:Receptors, Interleukin-9; D016897:Respiratory Burst / Q000187:drug effects / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000502:physiology*; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism*
D000276:Adjuvants, Immunologic; D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D005419:Flavonoids; C508045:IL9R protein, human; D016906:Interleukin-9; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D018123:Receptors, Interleukin; D053651:Receptors, Interleukin-9; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one