STAT1 deficiency redirects IFN signalling toward suppression of TLR response through a feedback activation of STAT3

• DOI: 10.1038/srep13414
• Publication Date: 2015-08-24T09:25:25Z
• Authors: Hun Sik Kim; Dong Chan Kim; Hong-Mi Kim; Hyung-Joon Kwon; Soon Jae Kwon; Suk-Jo Kang; Sun Chang Kim; Go-Eun Choi
• Keywords: STAT1

Abstract Interferons (IFNs) potentiate macrophage activation typically via a STAT1-dependent pathway. Recent studies suggest functioning of STAT1-independent pathway in the regulation gene expression by IFN-γ, thus pointing to diversity cellular responses IFNs. Many functions IFNs rely on cross-regulation exogenous inflammatory mediators such as TLR ligands. Here we investigated contribution and its underlying mechanism context combined stimulation IFN TLR. We found that TLR-induced production cytokines (TNF-α, IL-12) was not simply nullified but significantly suppressed signaling common IFN-γ IFN-β STAT1-null macrophages. Such shift suppression response correlated with sustained STAT3 attenuation NF-κB signaling. Using JAK2/STAT3 inhibitor or STAT3-specific siRNA, blocking restored TNF-α signaling, indicating functional among STAT1, NF-κB. Our results STAT1 deficiency reprograms from priming toward feedback STAT3, which may provide new insight into host defense against microbial pathogens situation deficiency.