Monocyte deactivation by interleukin 10 via inhibition of tyrosine kinase activity and the Ras signaling pathway.
Activation of monocytes by bacterial lipopolysaccharides (LPSs) is a central component in the pathogenesis of septic shock syndrome. Interleukin 10 (IL-10) is a potent monocyte-deactivating factor and transcriptionally inhibits LPS-induced expression of proinflammatory mediators. The intracellular signaling pathways of LPS have been only partially characterized and mechanisms of IL-10 signaling remain unknown. We show that LPS activates the protein tyrosine kinase (PTK) p56lyn and that this is associated with tyrosine phosphorylation of the protooncogene product Vav. These events are completely blocked by the tyrosine kinase inhibitor herbimycin A. LPS also increases Ras activation in monocytes. LPS-triggered phosphorylation of mitogen-activated protein kinase is a downstream activation event that is also reduced by herbimycin A. Analysis of the IL-10 effects shows that it completely inhibits the p56lyn tyrosine kinase activation and all other subsequent events in this pathway including Ras activation. The IL-10 effects are selective since it reduced PTK-dependent cytokine mRNA expression but not the PTK independent induction of c-jun and c-fos mRNA in LPS-activated monocytes. These results identify the Ras signaling pathway as a component of intracellular signaling in LPS-stimulated monocytes and define early events in this response as targets of monocyte deactivation by IL-10.
Geng
Y
Y
Department of Medicine, University of California at San Diego, La Jolla 92093.
Gulbins
E
E
Altman
A
A
Lotz
M
M
D001483:Base Sequence; D016227:Benzoquinones; D018797:Cell Cycle Proteins; D017931:DNA Primers / Q000737:chemistry; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D016758:Genes, jun; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1; D016753:Interleukin-10 / Q000502:physiology*; D047029:Lactams, Macrocyclic; D008070:Lipopolysaccharides / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1; D008969:Molecular Sequence Data; D009000:Monocytes / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*; D011809:Quinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction
D016227:Benzoquinones; D018797:Cell Cycle Proteins; D017931:DNA Primers; D007375:Interleukin-1; D047029:Lactams, Macrocyclic; D008070:Lipopolysaccharides; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D011809:Quinones; D012333:RNA, Messenger; C496618:VAV1 protein, human; D016753:Interleukin-10; D017828:Rifabutin; C020754:herbimycin; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)