title: Ameliorated ConA-induced hepatitis in the absence of PKC-theta.
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-θ(-/-) mice were resistant to ConA-induced hepatitis due to essential function of PKC-θ 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-θ(-/-) mice. Correspondingly, ConA-induced production of cytokines such as IFNγ, IL-6, and TNFα, which mediate the inflammation responsible for liver injury, were significantly lower in PKC-θ(-/-) mice. Peripheral NKT cells had developmental defects at early stages in the thymus in PKC-θ(-/-) mice, and as a result their frequency and number were greatly reduced. Furthermore, PKC-θ(-/-) bone marrow adoptively transferred to WT mice displayed similar defects in NKT cell development, suggesting an intrinsic requirement for PKC-θ in NKT cell development. In addition, upon stimulation with NKT cell-specific lipid ligand, peripheral PKC-θ(-/-) NKT cells produced lower levels of inflammatory cytokines than that of WT NKT cells, suggesting that activation of NKT cells also requires PKC-θ. Our results suggest PKC-θ is an essential molecule required for activation of NKT cell to induce hepatitis, and thus, is a potential drug target for prevention of autoimmune hepatitis.
authors.affiliation: Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, California, United States of America.
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Fang
authors.forename: Ruiqing
authors.initials: R
authors.lastname: Wang
authors.forename: Jian
authors.initials: J
authors.lastname: Ma
authors.forename: Yan
authors.initials: Y
authors.lastname: Ding
authors.forename: Weirong
authors.initials: W
authors.lastname: Shang
authors.forename: Zuoming
authors.initials: Z
authors.lastname: Sun
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy; D003208:Concanavalin A / Q000494:pharmacology*; D006520:Hepatitis, Animal / Q000139:chemically induced / Q000276:immunology*; D007249:Inflammation; D007527:Isoenzymes / Q000172:deficiency*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000473:pathology*; D011493:Protein Kinase C / Q000172:deficiency*; D000074121:Protein Kinase C-theta
chemical_list: D007527:Isoenzymes; D003208:Concanavalin A; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta