title: The ligands of translocator protein inhibit human Th1 responses and the rejection of murine skin allografts.
abstract: The translocator protein (TSPO) ligands affected inflammatory and immune responses. However, the exact effects of TSPO ligands on Th1 responses in vitro and in vivo are still unclear. In the present study, we found that TSPO ligands, FGIN1-27 and Ro5-4864, suppressed the cytokine production in a dose-dependent manner by purified human CD4+T-cells from peripheral blood mononuclear cells (PBMCs) after stimulation. TSPO ligands inhibited the production of interferon γ (IFN-γ) by memory CD4+T-cells and the differentiation of naïve CD4+T-cells into Th1 cells via suppressing the activity of the corresponding transcription factors as indicated by reduced expression of T-bet and down-regulation of STAT1, STAT4 and STAT5 phosphorylation. TSPO ligands suppressed cell proliferation and activation of CD4+T-cells by the inhibition of TCR signal transduction including membrane proteins: Zap, Lck, Src; cytoplasm proteins: Plcγ1, Slp-76, ERK, JNK and the nucleoproteins: c-Jun and c-Fos. In addition, FGIN1-27 inhibited mixed lymphocyte reactions by human or murine cells. After the transplantation of allogeneic murine skin, injection of FGIN1-27 into mice prevented graft rejection by inhibition of cell infiltration and IFN-γ production. Taken together, our data suggest that TSPO ligands inhibit Th1 cell responses and might be novel therapeutic medicine for the treatment of autoimmune diseases and prevention of transplant rejection.
authors.affiliation: Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology; Institute of Immunology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China.
authors.forename: Yannan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology; Institute of Immunology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China.
authors.forename: Sifei
authors.initials: S
authors.lastname: Yu
authors.affiliation: Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology; Institute of Immunology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Li
authors.affiliation: Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology; Institute of Immunology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China.
authors.forename: Binyan
authors.initials: B
authors.lastname: Yang
authors.affiliation: Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology; Institute of Immunology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China changyou_wu@yahoo.com.
authors.forename: Changyou
authors.initials: C
authors.lastname: Wu
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001570:Benzodiazepinones / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D007210:Indoleacetic Acids / Q000276:immunology / Q000627:therapeutic use*; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000276:immunology; D018079:Receptors, GABA / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D016038:Skin Transplantation; D020825:T-Box Domain Proteins / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology*; D055815:Young Adult; D000098815:T-bet Transcription Factor
chemical_list: D001570:Benzodiazepinones; C463819:Bzrp protein, mouse; D016207:Cytokines; D007210:Indoleacetic Acids; D008024:Ligands; D018079:Receptors, GABA; D050791:STAT Transcription Factors; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C499229:TSPO protein, human; C081306:N,N-di-n-hexyl-2-(4-fluorophenyl)indole-3-acetamide; C028513:4'-chlorodiazepam
keywords: CD4+ T-cells; TCR signal transduction; TSPO ligands; Th1 responses; skin allografts