Kolşisinin Pyrin ve Pyrin ile Ilişkili Proteinler Üzerine Etkisi

Abstract

MEFV which encodes pyrin, causes familial Mediterranean fever (FMF), the most common auto-inflammatory disease. Pyrin is believed to be a regulator of inflammation, though the nature of this regulatory activity remains to be identified. Prophylactic treatment with colchicine, a microtubule toxin, has had a remarkable effect on disease progression and outcome. It has been thought that, inhibition of microtubule polymerization is the main mechanism of action of colchicine. But, the exact cellular mechanism explaining the efficacy of colchicine in suppressing FMF attacks is still unclear. Given the ability of colchicine treatment to be considered as a differential diagnosis criteria of FMF. We hypothesized that colchicine may have a specific effect on pyrin and pyrin interacting proteins. This study showed that administration of 7,5 ng/ml colchicine reduces ASC speck rates in HeLa cells. Also it is demonstrated that 10 ng/ml colchicine prevents reticulated fibrils formed by Pyrin and PSTPIP1 in COS7 cells. We further noted that, colchicine down-regulates MEFV expression in THP-1 cells. We also observed that colchicine causes re-organization of actin cytoskeleton in THP-1 cells. Pyrin is an actin-binding protein that specifically localizes with polymerizing actin filaments. Thus, MEFV expression might be affected by reorganization of actin cytoskeleton. Finally, microarray experiments showed that colchicine administration change the expression levels of actin-related genes. Also some of these genes play regulatory roles in cell migration pathways. According to this, it has been thought that colchicine inhibits cell migration via inducing actin re-organization. In this study, the actions of colchicine on both cellular and transcriptional levels were identified. The data presented here reveal an important connection between colchicine and pyrin which might explain the remarkable efficacy of colchicine in preventing FMF attacks.