Negative regulation of MyD88-dependent signaling by IL-10 in dendritic cells

作者：Chang JiHoon; Kunkel Steven L; Chang Cheong Hee^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2009, 106(43): 18327-18332.

DOI：10.1073/pnas.0905815106

• cytokine
• ubiquitination
• endotoxin tolerance

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.

• 出版日期2009-10-27