ID: 62: Deletion of the IFN-gamma 3鈥?UTR AU-rich element results in autoimmune cholangitis in female C57/BL6 mice

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• 作者：Heekyong Bae¹ ; ; Julio C. Valencia¹ ; Deborah L. Hodge¹ ; Michael E. Sanford¹ ; Charlotte A. Hanson¹ ; Tim Back¹ ; Megan Karwan² ; Dechun Feng³ ; Bin Gao³ ; Ogyi Park⁴ ; Koichi Tsuneyama⁵ ; Patrick S. Leung⁶ ; M. Eric Gershwin⁶ ; Howard A. Young¹
• 刊名：Cytokine
• 出版年：2015
• 出版时间：November 2015
• 年：2015
• 卷：76
• 期：1
• 页码：76
• 全文大小：44 K

文摘

Primary biliary cirrhosis (PBC, now called autoimmune cholangitis) is an autoimmune liver disease and occurs primarily in women (mmlsi1" class="mathmlsrc">mulatext stixSupport mathImg" data-mathURL="/science?_ob=MathURL&_method=retrieve&_eid=1-s2.0-S1043466615003580&_mathId=si1.gif&_user=111111111&_pii=S1043466615003580&_rdoc=1&_issn=10434666&md5=c6f4f5358b80b77b10f672811a029d82" title="Click to view the MathML source">>mathContainer hidden">mathCode"><math altimg="si1.gif" overflow="scroll"><mrow><mo>>mo>mrow>math>90%), eventually leads to liver failure. IFN-gamma is elevated in patients with PBC, but the functional role of IFN-gamma on PBC is not known. Here, we characterized the distinctive pathological phenotype of PBC in a mouse model of chronic IFN-gamma expression generated by deletion of the IFN-gamma 3&prime; UTR AU-rich element (ARE-Del). Consistent with clinical features seen in PBC, female ARE-Del mice have moderate immune cell infiltration and bile duct destruction near hepatic portal tracts with dramatically upregulated bile acids and spontaneous production of anti-mitochondria antibodies in serum. In contrast, male ARE-Del have relatively mild histological and serological evidences of PBC compared to female ARE-Del. By focusing on genes whose expression is highly specific to female ARE-Del, type I interferon receptor and dendritic maturation are top upstream pathways for this female specific disease progression. Remarkably, deletion of the interferon a/b receptor in ARE-Del mice significantly suppressed the female-specific pathological phenotypes, specifically eliminating the sex-different phenotypes in PBC. Furthermore, female ARE-Del have notably increased plasmacytoid dendritic cells (pDC), specialized in massive secretion of type I interferon (IFN alpha and beta), suggesting that increased type I interferon via pDC is critical for the sex-difference in this disease progression. Taken together, the ARE-Del is the first mice model to present the sex differences seen in PBC and startlingly demonstrates how type II interferon coordinates with type I interferon in this disease progression.