IFN-γ is a pleiotropic cytokine importantly involved in the development of skin inflammatory responses. Epidermal keratinocytes are extremely susceptible to IFN-γ action, but, once transduced with the suppressors of cytokine signaling (SOCS)1 molecule, they can no longer express a number of IFN-γ-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-γ. Here we show that, after IFN-γ stimulation, SOCS1 inhibited IFN-γ receptor and STAT1 phosphorylation but maintained ERK1/2 activation. SOCS1 was also necessary for the IFN-γ-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-γ, 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-γ stimulation. We hypothesize that SOCS1 functions as suppressor of IFN-γ signaling, not only by inhibiting STAT1 activation but also by sustaining ERK1/2-dependent antiinflammatory pathways.
- Antiinflammatory pathways
- Skin immune responses
- Skin inflammation
ASJC Scopus subject areas
- Agricultural and Biological Sciences (miscellaneous)
- Biochemistry, Genetics and Molecular Biology(all)
- Cell Biology