Janus kinase 3 down-regulates lipopolysaccharide-induced IL-1 beta-converting enzyme activation by autocrine IL-10.
ProIL-1 beta processing by IL-1 beta-converting enzyme (ICE) and the subsequent release of mature IL-1 beta are highly regulated events in the monocyte/macrophage response to pathogens. This process occurs in a controlled way through the activation of the constitutively expressed 45-kDa ICE precursor (proICE). To characterize the signaling pathways involved in ICE regulation in human monocytes/macrophages, we analyzed ICE activation in the presence of specific inhibitors of classic signaling pathways. Although LPS-induced ICE activity was not significantly affected by interruption of extracellular signal-regulated kinase, p38 kinase, or phosphoinositol 3-kinase, Janus kinase 3 (JAK3) inhibition produced a significant dose-dependent enhancement of LPS-induced ICE activity. Support for the inhibitory role of JAK3 was shown by the fact that IL-4 (which uses JAK1 and JAK3 signaling) suppressed LPS-induced ICE activity and by the finding that JAK3 knockout macrophages have increased LPS-induced ICE activation. To understand how JAK3 down-regulates LPS-induced ICE activity in monocytes, we hypothesized that JAK3 signaling enhances IL-10 production. In support of this model we show that LPS-induced IL-10 expression was synchronous with ICE deactivation, IL-4 induced the release of IL-10, exogenous IL-10 suppressed LPS-induced ICE activity, a neutralizing IL-10 Ab increased LPS-induced ICE activity, and, finally, JAK3 knockout macrophages displayed significantly reduced LPS-induced IL-10 production. These findings support a model in which JAK3 signaling enhances IL-10 production leading to down-regulation of ICE activation and suppression of IL-1 beta processing and release.
Kim
Hee-Jung
HJ
Division of Pulmonary and Critical Care Medicine, and Davis Heart and Lung Research Institute, Ohio State University, Columbus, OH 43210, USA.
Hart
Judy
J
Knatz
Nina
N
Hall
Mark W
MW
Wewers
Mark D
MD
D000818:Animals; D019898:Autocrine Communication / Q000276:immunology*; D020170:Caspase 1 / Q000096:biosynthesis / Q000378:metabolism*; D061945:Caspase Inhibitors; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology*; D004789:Enzyme Activation / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D053616:Janus Kinase 3; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000201:enzymology / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D011799:Quinazolines; C116180:WHI P131; D016753:Interleukin-10; D015847:Interleukin-4; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3; D020170:Caspase 1