| Tenascin-C(TN-C) is an extracellular matrix glycoprotein, which is specifically and transiently expressed in tissue injuries and interacts with a variety of ECM molecules and cell surface receptors. TN-C is not found in normal adult tissues,whereas transient TN-C expression is often induced with acute inflammation and tissue damage,and is down-regulated concomitant with the resolution of inflammation and tissue repair. Studies have shown that TN-C played a key role in prolonging joint inflammation.Tn-C-/- mice shoued less sustained and erosive joint inflammation, including attenuated paw swelling and reduced cell infiltration. And inflammation was induced after intra-articular. In Rheumatoid Arthritis(RA) patients, TN-C was highly expressed in cartilage and synorial membrance. RA is a chronic autoimmune inflammatory disease, occuring a destructive inflammation in joints and surrounding tissue, and cilical manifestations is joint dissability. In all, synovial fibroblast proliferation and immune cells(especially macrophages)infliltration are believed to be the pathological basis.Monocytes originate in the bone marrow, circulate in the peripheral blood and enter tissues to replenish tissue-specific macrophages, which constituting monocyte/macrophage system. Macrophages involve in RA mainly by atcing as antigen presenting cells and secreting a variety of cytokines and chemokines including TNF-α and IL-1,and TNF-α antibody was such an efective candidate to be applied to treat RA in clinical therapy. Interestingly, high levels of TN-C were expressed in pathogenic foci in the synovium of RA patients, correlating with inflammatory cell infiltration. And TN-C was believed to be a key pro inflammatory mediator in the RA joint. However, there were some issues remain to be discovered: ①where is the origin of the high levels of TN-C in the joint? ②whether it can alleviate the symptoms of arthritis by inhibiting the expression of TN-C in macrophages.We speculated that the inccreased TN-C in arthritis synovail might originate from infltrated macrophages,thus inhibiting the expresssion of TN-C in monocyte/macrophage would be helpful to treat RA. Fc99 is a small chemosynthesis molecule, and previous studies in our laboratory reported that Fc99 had anti-inflammatory effects, and we were prompted to aspect Fc99 to be able to inhibit expression of TN-C in macrophages. In this study, we explored the expression of TN-C in macrophages after LPS(lipopolysaccharride)induction in vitro, and evaluated TN-C expression after Fc99 treatment. Fuethermore, we assessed the efficacy of Fc99 in Zymosan-induced arthritis(ZIA)mice model.The results showed that the cell surface receptor CD14 and CD11b could increase after PMA stimulation in THP-1 monocytes, confirming the transform of THP-1 monocyte to macrophage. LPS could drastically inhibit the expression of TN-C in THP-1 macrophage, and small molecule Fc99 could significantly inhibit the expresion of TN-C both on mRNA and protein levels. Similaarly, Fc99 showed the same effects in RAW264.7 mouse macrophage. Furtherly, we transfected 293T cell by TN-C(FBG domain)plasmid, and discovered Fc99 could also inhibit TN-C overexpression in 293T cell. In vivo data found that Fc99 alleviated the syptoms of arthritis in mice by reducing paw swelling and inflammation cells infiltration in joints. RT-QPCR showed that Fc99 effectively inhibited TN-C expression in joint tissue.In conclusion, we found that Fc99 can could effectively suppress the expression of TN-C in macrophage after LPS induction, and it also could drastically relieved joint injuries by reducing TN-C expression in ZIA mice. Thus Fc99 might become a candicdate for treating inflammatory disorders. |
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