The Regulation Mechanisms Of β-arrestin 2 In The Pathogenesis Of Primary Biliary Cirrhosis

This study is to investigate the regulations ofβ-arrestin 2 on autoimmune responses and autoimmune related genes in primary biliary cirrhosis(PBC), and elucidate the molecular regulatory mechanisms ofβ-arrestin 2 in disease course of PBC , providing a clue for novel treatment of PBC. Firstly, the expression ofβ-arrestin 2 in peripheral blood mononuclear cells (PBMCs) of patients with PBC were detected by real-time quantitative PCR and western-blotting, from the levels of genetic transcription and protein expression respectively. Secondly, we induced PBC mice models by poly I:C injection inβ-arrestin 2 overexpression mice andβ-arrestin 2 knock out mice, to make sure thatβ-arrestin 2 involves in the pathogenesis of PBC. Thirdly, PDC-E2-specific autoreactive cytotoxic T lymphocytes(CTLs) from PBMCs of patients with PBC were prepared, and then transfected with plasmids of pcDNA3/β-arrestin 2 and pBS/U6/β-arrestin 2siRNA respectively. The impact of silencing and overexpressing ofβ-arrestin 2 on cell proliferation, cytotoxity, activation induced cell death(AICD), expression of autoimmune related genes,such as TNFSF8 and CCL2, and acetylation of histone H4 at the promoters of these autoimmune related genes were investigated, so as to explore the regulatory effets ofβ-arrestin 2 on PDC-E2-specific autoreactive CTLs. The results showed that the expression ofβ-arrestin 2 decreased remarkablely in PBMCs of patients with PBC, especially in CD4+T,CD8+T cells and monocytes;β-arrestin 2 could inhibit the PBC-like disease course induced by poly I:C injection; In PDC-E2-specific autoreactive CTLs derived from PBMCs of patients with PBC,β-arrestin 2 could negatively regulate cell proliferation, cytotoxity, activation induced cell death(AICD), and modulate the expressions of some autoimmune related genes,such as TNFSF8 and CCL2, by regulating the acetylation level of histone H4 at promoters of these genes. Therefore,β-arrestin 2 may function as negative regulator in the course of PBC, be involved in the pathogenesis of PBC by downregulating acetylation level of histone H4 at promoters of autoimmune related genes.