SOCS1 kinase inhibitory region peptide mimics regulate interferon gamma and TLR7-induced inflammatory signatures in murine macrophages.

Although it is known that SOCS1 can modulate JAK/STAT signaling through both its kinase inhibitory region (KIR) and SOCS box domain, and limit toll-like receptor (TLR) induced inflammation via the SOCS1 box domain, the relative contribution of the KIR domain to TLR regulation is not well understood. In this study, we utilized peptide mimics of SOCS1 KIR to study the effect of the KIR domain in modulating TLR7 and interferon γ (IFNγ) signaling in murine primary macrophages and cell lines. We found that SOCS1 KIR mimetics were able to inhibit, by up to 50%, the inflammatory signatures associated with TLR7 stimulation, IFNγ stimulation, and the enhanced IFNγ-induced gene signature, mediated by TLR7 and IFNγ co-treatment. While inhibition of IFNg mediated activation correlated with reduced Y701 phosphorylation on STAT1 and Y705 phosphorylation on STAT3, the inhibition of TLR7-induced inflammation and the TLR7-enhanced IFNγ-induced gene signature coincided with a reduction in both Y701 and S727 phosphorylation on the STAT1 transactivation domain. Altogether, we report for the first time a novel role of the SOCS1 KIR domain in regulating TLR7-mediated, and TLR7-enhanced IFNγ-mediated, inflammation.