SOCS1/JAB Is a Negative Regulator of LPS-Induced Macrophage Activation

Abstract

Bacterial lipopolysaccharide (LPS) triggers innate immune responses through Toll-like receptor (TLR) 4. We show here that the suppressor of cytokine-signaling-1 (SOCS1/JAB) is rapidly induced by LPS and negatively regulates LPS signaling. SOCS1(+/-) mice or SOCS1(-/-) mice with interferon-gamma (IFNgamma)-deficient background were more sensitive to LPS-induced lethal effects than were wild-type littermates. LPS-induced NO(2)(-) synthesis and TNFalpha production were augmented in SOCS1(-/-) macrophages. Furthermore, LPS tolerance, a protection mechanism against endotoxin shock, was also strikingly reduced in SOCS1(-/-) cells. LPS-induced I-kappaB and p38 phosphorylation was upregulated in SOCS1(-/-) macrophages, and forced expression of SOCS1 suppressed LPS-induced NF-kappaB activation. Thus, SOCS1 directly suppresses TLR4 signaling and modulates innate immunity.

Albaconol, a Plant-Derived Small Molecule, Inhibits Macrophage Function by Suppressing NF-κB Activation and Enhancing SOCS1 Expression

“…LPS-induced IκB and p38 phosphorylation was up-regulated in SOCS1 -/-macrophages and forced expression of SOCS1 suppressed LPS-induced NF-κB activation (18). Since the expressions of proinflammatory mediators and the activity of NF-κB are known to be modulated by SOCS1, we found that albaconol could induce SOCS1 up-regulation in RAW264.7 cells stimulated by LPS, thus outlining one of mechanistic explanation for the antiinflammatory effect of albaconol.…”

“…Recently, SOCS1 was found to be induced by LPS stimulation in macrophages (16) and it is reported that SOCS1 is an essential down-regulating factor for protecting host from fatal responses to LPS (17). Particularly, SOCS1 overexpression suppressed LPS-induced IκB phosphorylation and NF-κB transcriptional activity (18). Therefore, to determine if albaconol could induce SOCS1 expression to suppress LPS signaling, we analyzed LPS-induced expression of SOCS1 in RAW264.7 cells pretreated with albaconol.…”

BAFF synthesis by rheumatoid synoviocytes is positively controlled by α5β1 integrin stimulation and is negatively regulated by tumor necrosis factor α and toll‐like receptor ligands

“…Whereas SOCS-1 functions by binding directly to JAK proteins, SOCS-3 binds to phosphorylated tyrosine on the receptor. SOCS-1 and SOCS-3 are also induced by JAK/STAT-independent stimuli, such as LPS, CpG, TNF␣, and insulin (36,37). Indeed, we demonstrated that costimulation with either LPS or TNF␣ enhanced SOCS-1 and SOCS-3 mRNA expression.…”

NF-κB and the immune response

“…Interestingly, SIGIRR is also highly expressed in epithelial cells, suggesting that it too may suppress signaling at sites of constitutive microbial exposure. Finally, suppressor of cytokine signaling-1 (SOCS-1) has been reported to negatively regulate LPS signaling to NF-kB and socs1 À/À mice exhibit an inflammatory phenotype that is consistent with this prediction (Kinjyo et al, 2002;Nakagawa et al, 2002). SOCS-1 may function by directly targeting TIRAP/Mal, and selectively inhibit TLR4 signaling through the TIRAP/Mal/MyD88 pathway (Mansell et al, 2006).…”