ameliorated cona-induced hepatitis in the absence of pkc-theta改善cona-induced肝炎没有pkc-theta.pdfVIP

Ameliorated ConA-Induced Hepatitis in the Absence of PKC-theta 1 1 1 1 2 1 Xianfeng Fang , Ruiqing Wang , Jian Ma , Yan Ding , Weirong Shang , Zuoming Sun * 1 Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, California, United States of America, 2 Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Georgia, United States of America Abstract Severe liver injury that occurs when immune cells mistakenly attack an individual’s own liver cells leads to autoimmune hepatitis. In mice, acute hepatitis can be induced by concanavalin A (ConA) treatment, which causes rapid activation of CD1d-positive natural killer (NK) T cells. These activated NKT cells produce large amounts of cytokines, which induce strong inflammation that damages liver tissues. Here we show that PKC-h2/ 2 mice were resistant to ConA-induced hepatitis due to essential function of PKC-h in NKT cell development and activation. A dosage of ConA (25 mg/kg) that was lethal to wild- type (WT) mice failed to induce death resulting from liver injury in PKC-h2/ 2 mice. Correspondingly, ConA-induced production of cytokines such as IFNc, IL-6, and TNFa, which mediate the inflammation responsible for liver injury, were significantly lower in PKC-h2/ 2 mice. Peripheral NKT cells had developmental defects at early stages in the thymus in PKC- h2/ 2 mice, and as a result their frequency and number were greatly reduced. Furthermore, PKC-h2/ 2 bone marrow adoptively transferred to WT mice displayed similar defects in NKT cell development, suggesting an intrinsic requirement for PKC-h