CXCL9 and CXCL11 chemokines modulation by peroxisome proliferator-activated receptor-alpha agonists secretion in Graves' and normal thyrocytes.

CONTEXT: Peroxisome proliferator-activated receptor (PPAR)-α has been shown to exert immunomodulatory effects in autoimmune disorders. However, until now, no data were present in the literature about the effect of PPARα activation on CXCL9 and CXCL11 chemokines in general or on secretion of these chemokines in thyroid cells. OBJECTIVE AND DESIGN: The presence of PPARα and PPARγ has been evaluated by real-time-PCR in Graves' disease (GD) and control cells in primary culture. Furthermore, we have tested the role of PPARα and PPARγ activation on CXCL9 and CXCL11 secretion in GD and control cells after stimulation of these chemokines secretion with IFNγ and TNFα. RESULTS: This study shows the presence of PPARα and PPARγ in GD and control cells. A potent dose-dependent inhibition by PPARα-agonists was observed on the cytokines-stimulated secretion of CXCL9 and CXCL11 in GD and control cells. The potency of the PPARα agonists used was maximum on the secretion of CXCL9, reaching about 90% of inhibition by fenofibrate and 85% by ciprofibrate. The relative potency of the compounds was different with each chemokine; for example, gemfibrozil exerted a 55% inhibition on CXCL11, whereas it had a weaker activity on CXCL9 (40% inhibition). PPARα agonists were stronger (ANOVA, P<0.001) inhibitors of CXCL9 and CXCL11 secretion in thyrocytes than PPARγ agonists. CONCLUSIONS: Our study shows the presence of PPARα in GD and control thyrocytes. PPARα activators are potent inhibitors of the secretion of CXCL9 and CXCL11, suggesting that PPARα may be involved in the modulation of the immune response in the thyroid.

Proinflammatory effects of muramyldipeptide on human gingival fibroblasts.

BACKGROUND AND OBJECTIVE: Because human gingival fibroblasts (HGFs) are the predominant cells in periodontal tissues, we hypothesized that HGFs are contributed to receptors for components of bacteria. In this study, we focused on expression and function of nucleotide binding oligomerization domain 2 (NOD2) in HGFs, which is a mammalian cytosolic pathogen recognition molecule. MATERIAL AND METHODS: Expression of NOD2 in HGFs was examined by reverse transcriptase-polymerase chain reaction (RT-PCR) and flow cytometry. Production of interleukin (IL)-6, IL-8, cc chemokine ligand2, cxc chemokine ligand10 (CXCL10) and CXCL11 from HGFs was examined by enzyme-linked immunosorbent assay (ELISA). We used RT-PCR and immunohistochemistry to detect the NOD2 expression in human gingival tissues. RESULTS: We found clear NOD2 expression in HGFs. Upon stimulation with NOD2 agonist, muramyldipeptide (MDP), production of proinflammatory cytokines was enhanced. Moreover, MDP-induced production of proinflammatory cytokines was inhibited in a different manner by mitogen-activated protein kinase inhibitors and phosphatidylinositol 3-kinase inhibitor. Furthermore, MDP enhanced CXCL10 and CXCL11 productions by tumor necrosis factor-alpha (TNF-alpha)- or interferon-gamma (IFN-gamma)-stimulated HGFs, although MDP alone did not induce these chemokines. TNF-alpha and IFN-gamma increased NOD2 expression in HGFs. In addition, we detected NOD2 expression in mononuclear cells and HGFs in periodontally diseased tissues. CONCLUSION: These findings indicate that MDP which induces production of cytokines and chemokines from HGFs is related to the pathogenesis of periodontal disease.