Negative regulation of MyD88-dependent signaling by IL-10 in dendritic cells.
IL-10 produced by dendritic cells (DC) can limit or terminate ongoing inflammatory responses by inhibiting the proinflammatory cytokine production. Currently, the molecular mechanism by which IL-10 suppresses cytokine production is still ill-defined. In this study, we showed that IL-10 produced by DC dampens myeloid differentiation factor (MyD)88-dependent, but not MyD88-independent signaling. At the molecular level, IL-10 induces ubiquitination and subsequent protein degradation of MyD88-dependent signaling molecules, including IL-1 receptor-associated kinase 4 and TNF-receptor associated factor 6. Protein degradation by IL-10 was associated with decreased phosphorylation of p38, JNK, and IKK. All of these events were prevented by either blocking IL-10 receptor signaling or inhibiting proteasome degradation. IL-10 induced LPS hyporesponsiveness using the same mechanisms, i.e., ubiquitination and protein degradation. Thus, a previously undescribed regulatory mechanism by which IL-10-mediated protein degradation contributes to the inhibition of inflammatory cytokine production and endotoxin tolerance in DC.
Chang
Jihoon
J
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Kunkel
Steven L
SL
Chang
Cheong-Hee
CH
D000818:Animals; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D004731:Endotoxins / Q000276:immunology; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000172:deficiency / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015398:Signal Transduction; D054875:Ubiquitination
D004731:Endotoxins; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D016753:Interleukin-10; D046988:Proteasome Endopeptidase Complex