Triggering of Toll-like receptors modulates IFN-gamma signaling: involvement of serine 727 STAT1 phosphorylation and suppressors of cytokine signaling.
Microbial stimuli activate cells of the innate immune system by triggering Toll-like receptors (TLR). Activation of macrophages and dendritic cells is further enhanced by secondary signals like IFN-gamma. Here we analyzed the interplay of IFN-gamma and TLR signaling in cells of the innate immune system. Using a STAT1-dependent reporter construct we show that IFN-gamma signaling can be enhanced as well as inhibited by simultaneous stimulation with either defined TLR agonists or whole-bacterial lysates. Short costimulation resulted in the amplification of IFN-gamma signaling and was attributable to the p38 mitogen-activated protein kinase (MAPK)-dependent phosphorylation of signal transducer and activator of transcription (STAT)1 on serine 727. In contrast, prolonged co-incubation as well as pre-incubation with TLR agonists led to an inhibition of IFN-gamma signaling. TLR triggering induced expression of suppressor of cytokine signaling (SOCS)-1, SOCS-3 and cytokine-inducible SH2 domain-containing protein (CIS). Overexpression of SOCS-1 and, to a lesser extend, of SOCS-3 and CIS inhibited IFN-gamma signaling as measured by activation of STAT1. Moreover, pre-incubation with TLR-dependent stimuli impaired IFN-gamma-induced MHC class II regulation but enhanced CD40 and CD86 expression. Taken together, the results indicate a tight interplay between TLR and IFN-gamma signaling pathways which involve induction of SOCS proteins and serine phosphorylation of STAT1.
Dalpke
Alexander H
AH
Institute of Medical Microbiology and Hygiene, Philipps-University Marburg, Pilgrimstein 2, D-35037 Marburg, Germany.
Eckerle
Susan
S
Frey
Markus
M
Heeg
Klaus
K
D015703:Antigens, CD / Q000378:metabolism; D051940:B7-2 Antigen; D019013:CD40 Antigens / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008264:Macrophages / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D012694:Serine / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051193:Toll-Like Receptors; D015534:Trans-Activators / Q000378:metabolism*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases
D015703:Antigens, CD; D051940:B7-2 Antigen; D019013:CD40 Antigens; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D000949:Histocompatibility Antigens Class II; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; C108944:SOCS1 protein, human; D050794:STAT1 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051193:Toll-Like Receptors; D015534:Trans-Activators; D012694:Serine; D007371:Interferon-gamma; D048051:p38 Mitogen-Activated Protein Kinases