Suppressor of cytokine signaling-1 selectively inhibits LPS-induced IL-6 production by regulating JAK-STAT

Abstract

Suppressor of cytokine signaling-1 (SOCS-1) is one of the negative-feedback regulators of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. We previously showed that SOCS-1 participates in LPS signaling, but it is not entirely clear yet how SOCS-1 suppresses LPS signaling. In this study, we demonstrate that SOCS-1 selectively inhibits LPS-induced IL-6 production through regulation of JAK-STAT but not production of TNF-a, granulocyte colony-stimulating factor, IFN-β, and other cytokines. We found that LPS directly activated Jak2 and StatS, whereas SOCS-1 inhibited LPS-induced Jak2 and StatS activation. Further-more, AG490, a Jak-specific inhibitor, and dominant negative StatS only reduced LPS-induced IL-6 production. Additionally, StatS interacted with p50, resulting in recruitment of StatS to the IL-6 promoter together with p50 in response to LPS stimulation. These findings suggest that the JAK-STAT pathway participates in LPS-induced IL-6 production and that SOCS-1 suppresses LPS signaling by regulating JAK-STAT. © 2005 by The National Academy of Sciences of the USA.