Suppressor of cytokine signaling 1 inhibits IFN-gamma inflammatory signaling in human keratinocytes by sustaining ERK1/2 activation.
IFN-gamma is a pleiotropic cytokine importantly involved in the development of skin inflammatory responses. Epidermal keratinocytes are extremely susceptible to IFN-gamma action, but, once transduced with the suppressors of cytokine signaling (SOCS)1 molecule, they can no longer express a number of IFN-gamma-inducible signal transducer and activator of transcription (STAT)1-dependent genes. Extracellular-signal-regulated kinase (ERK)1/2 pathway is also involved in the protection of keratinocytes from the proinflammatory effect of IFN-gamma. Here we show that, after IFN-gamma stimulation, SOCS1 inhibited IFN-gamma receptor and STAT1 phosphorylation but maintained ERK1/2 activation. SOCS1 was also necessary for the IFN-gamma-induced RAS and Raf-1 activities in keratinocytes. The enhanced ERK1/2 pathway in SOCS1-overexpressing keratinocytes was in part responsible for their inability to respond to IFN-gamma, in terms of CXCL10 and CCL2 production, and for the high production of CXCL8. Moreover, SOCS1 interacted with the RAS inhibitor p120 RasGAP and promoted its degradation after IFN-gamma stimulation. We hypothesize that SOCS1 functions as suppressor of IFN-gamma signaling, not only by inhibiting STAT1 activation but also by sustaining ERK1/2-dependent antiinflammatory pathways.
Laboratory of Immunology, IDI-IRCCS, Via Monti di Creta, 104, 00167 Rome, Italy.
Stefania
S
Madonna
Claudia
C
Scarponi
Ornella
O
De Pità
Cristina
C
Albanesi
D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis; D054357:Chemokine CXCL10 / Q000096:biosynthesis; D004789:Enzyme Activation; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors*; D016209:Interleukin-8 / Q000378:metabolism; D015603:Keratinocytes / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000502:physiology*; D015854:Up-Regulation; D020729:p120 GTPase Activating Protein / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
C111835:CCL2 protein, human; C114753:CXCL10 protein, human; C508606:CXCL8 protein, human; D018932:Chemokine CCL2; D054357:Chemokine CXCL10; D016209:Interleukin-8; C108944:SOCS1 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D020729:p120 GTPase Activating Protein; D007371:Interferon-gamma; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D018631:ras Proteins