Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3 (Nature Immunology, 6:777-784, August 2005)

報告日期: 2005/09/27
報告時間: 17:10/18:00
報告學生: 陳韻如
講評老師: 徐麗君

Toll-like receptor–mediated cytokine production is differentially regulated by glycogen synthase kinase 3

     Michael Martin, Kunal Rehani, Richard S Jope, and Suzanne M Michalek

Nat. Immunol. 6: 777-784, 2005

Commentator: 徐麗君 老師                    Date: 2005/09/27 pm 5:10-6:00

Speaker: 陳韻如                              Room: 602



 Toll-like receptors (TLRs) are crucial for their ability to discriminate among distinct molecular patterns associated with microbial components in modulating immune responses. Recognition of microbial products by TLRs leads to a variety of signal transduction pathways that regulate the nature, magnitude and duration of the inflammatory response, such as PI(3)K-Akt pathway. However, the underlying cellular mechanisms that directly control pro- versus anti-inflammatory cytokine production after TLR stimulation are unresolved at present. In this paper, the authors identified glycogen synthase kinase 3 (GSK3), an effector molecule of PI(3)K, involved in TLR4 signaling. In response to TLR4 stimulation, inhibition of GSK3 selectively augmented production of anti-inflammatory interleukin 10 (IL-10), while concurrently suppressing production of pro-inflammatory cytokine, such as interleukin 12 (IL-12). Futhermore, the similar results were also observed in monocytes or peripheral blood mononuclear cells stimulated with TLR2, TLR5, or TLR9 agonists, suggesting that the regulation of pro- and anti-inflammatory cytokine production by GSK3 after TLR stimulation is a more global phenomenon. In addition, GSK3 regulated the TLR-induced inflammatory response mainly through increasing the binding of CREB and suppressing the binding of NF-κB to the nuclear coactivator CBP. Administration of a GSK3 inhibitor potently suppressed the proinflammatory response in mice receiving lipopolysaccharide and mediated protection from endotoxin shock. Taken together, these findings identify a critical function for GSK3 in modulating production of pro- versus anti-inflammatory cytokines in vivo and provide a rationale for regulating the nature and severity of inflammation. 


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