Synergistic induction of CCL5, CXCL9 and CXCL10 by IFN-gamma and NLRs ligands on human fibroblast-like synoviocytes-A potential immunopathological mechanism for joint inflammation in rheumatoid arthritis

摘要

Interferon-gamma (IFN-gamma) is traditionally regarded as a proinflammatory cytokine by virtue of its strong macrophage activating potential and its association with Th1 driven immune responses. NOD1 and NOD2 are cytoplasmic receptors that can initiate the initial immune response by sensing bacterial components or danger signals. In this study, we investigated the immunopathological roles of IFN-gamma and NOD1, 2 ligands iE-DAP/MDP on the activation of fibroblast-like synoviocytes (FLS) in RA. FLS constitutively express functional NOD1 and NOD2, and the gene and protein expression of NOD1 and NOD2 could be enhanced by the treatment with IFN-gamma. The synergistic effect was observed in the combined treatment of IFN-gamma and NOD1 ligand iE-DAP or NOD2 ligand MDP on the release of CCL5, CXCL9 and CXCL10 from FLS, and its effect was in a dose-dependent manner. The co-stimulation which IFN-gamma combined with iE-DAP/MDP could abolish the inhibition of CXCL8 level by IFN-gamma alone. Further investigations showed that synergistic effects on the production of CCL5, CXCL9 and CXCL10 in FLS stimulated by IFN-gamma and iE-DAP/MDP were differentially regulated by intracellular activation of NF-kappa B, p38MAPK and ERK pathways. In conclusion, our data confirmed the inflammatory effect of IFN-gamma and iE-DAP/MDP on human FLS for the first time and therefore provided a new insight into the IFN-gamma combined with NOD1 or NOD2 activated immunopathological mechanisms mediated by distinct intracellular signal transduction in joint inflammation of RA.