In this study, we addressed these issues by examining the protect

In this study, we addressed these issues by examining the protective role of VSIG4 in concanavalin A (ConA)-induced hepatitis using VSIG4 wildtype (WT) and knockout (KO) mice and analyzing the effect of VSIG4+ KCs on the induction of liver T- and NKT-cell tolerance using ovalbumin (OVA)-induced

and α-galactosylceramide (α-GalCer)-induced tolerance models. We demonstrated that the absence of VSIG4 greatly reduced survival rates and resulted in severe hepatitis upon ConA challenge, and impaired the induction of liver T- and NKT-cell tolerance. We also found that G1 phase-specific Cdk2, Cdk4, and Cdk6 were down-regulated and tolerance-inducing p27KIP-1 was up-regulated in T-cells costimulated with VSIG4.Ig. Thus, the present study provides evidence that selleck kinase inhibitor VSIG4 contributes to KC-mediated

liver T- and NKT-cell tolerance. α-GalCer, α-galactosylceramide; ALT, alanine aminotransferase; APCs, antigen presenting cells; CIH, concanavalin A-induced hepatitis; ConA, concanavalin A; DCs, dendritic cells; HSCs, hepatic stellate cells; KCs, Kupffer cells; LSECs, liver sinusoid endothelial cells; NKT-cells, natural killer T cells; PGE2, prostaglandin E2; Tregs, regulatory T cells; VSIG4, V-set and Ig domain-containing 4. Balb/c and C57BL/6 mice (8-10 weeks old) and LY5.1 congenic mice were purchased from the Jackson Laboratory. VSIG4 KO mice were generously provided by Dr. Campagne (Genentech). Mice were maintained under specific pathogen-free conditions in our animal facilities and received humane care under a protocol approved by the Institutional Animal Care and Use MCE公司 Committee of Inje University. ConA, bromodeoxyuridine

(BrdU), OVA protein, complete Freund’s adjuvant, DNase, and collagenase were purchased from Sigma-Aldrich. α-GalCer (KRN 7000) was purchased from Alexis Biochemicals. OVA323-339 peptide was synthesized by Peptron. FITC-, PE-, PE Cy5-, or APC-conjugated anti-CD45.1 (A20), anti-TCR-β (H57-597), anti-NK1.1 (NKR-PIC), anti-CD11b (M1/70), anti-CD11c (N418), anti-F4/80 (BM8), anti-CD146 (ME-9F1), anti-I-Ad (39-10-8), anti-CD80 (16-10A1), anti-CD86 (GL1), anti-B7-H1 (M1H5), anti-CD44 (IM7), anti-CD62L (MEL-14), anti-CD4 (L3T4), anti-IFN-γ (XMG1.2), anti-tumor necrosis factor alpha (TNF-α) (MP6-XT22), anti-IL-4 (11B11), anti-IL-17A (TC11-18H10.1), anti-FoxP3 (FJK-16S), anti-BrdU, and 7-AAD were obtained from eBioscience or BD Pharmingen. Anti-FITC, anti-CD11c, and anti-CD90.2 microbeads were purchased from Miltenyi Biotech. Antibodies against Rb, p130, E2F-1, E2F-4, cyclin D1, cyclin E, Cdk2, Cdk4, Cdk6, p53, p16INI4a, p21Waf1/Cip1, and p27Kip1 were purchased from Santa Cruz Biotechnology. Antibody against VSIG4 (14G8) that blocks the binding of C3b to VSIG4 was a kind gift from Dr. Campagne (Genentech).

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