IFN-gamma suppresses IL-10 production and synergizes with TLR2 by regulating GSK3 and CREB/AP-1 proteins.
The control of IL-10 production and mechanisms that mediate synergy between IFN-gamma and TLR ligands are not well understood. We report that IFN-gamma augments induction of TNFalpha by TLR ligands, immune complexes, and zymosan by suppressing IL-10 production and thereby interrupting Stat3-mediated feedback inhibition. IFN-gamma altered TLR2-induced signal transduction by increasing GSK3 activity and suppressing MAPK activation, leading to diminished IL-10 production. Inhibition of GSK3 or ablation of the GSK3beta gene ameliorated TLR2-induced peritonitis and arthritis. IFN-gamma suppressed the activity of CREB and AP-1, transcription factors that induce IL-10 expression and are regulated in part by MAPKs and GSK3. These results yield insight into mechanisms by which IFN-gamma regulates IL-10 production and TLR2-mediated inflammatory responses and identify inhibition of CREB and AP-1 as part of the macrophage response to IFN-gamma. GSK3 and CREB/AP-1 are key players in integrating IFN-gamma and TLR2 responses in innate immunity and inflammation.
Hu
Xiaoyu
X
Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, Weill Graduate School of Medical Sciences of Cornell University, New York, New York 10021, USA.
Paik
Paul K
PK
Chen
Janice
J
Yarilina
Anna
A
Kockeritz
Lisa
L
Lu
Theresa T
TT
Woodgett
James R
JR
Ivashkiv
Lionel B
LB
D000818:Animals; D001168:Arthritis / Q000276:immunology; D050882:CREB-Binding Protein / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D038362:Glycogen Synthase Kinase 3 / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000276:immunology; D051379:Mice; D018448:Models, Immunological; D010538:Peritonitis / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051195:Toll-Like Receptor 2 / Q000276:immunology* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000276:immunology* / Q000378:metabolism; D014162:Transfection
D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051195:Toll-Like Receptor 2; D018808:Transcription Factor AP-1; D016753:Interleukin-10; D007371:Interferon-gamma; D050882:CREB-Binding Protein; D038362:Glycogen Synthase Kinase 3