Impaired T cell-mediated hepatitis in peroxisome proliferator activated receptor alpha (PPARα)-deficient mice
Hines, Ian N.; Kremer, Michael; Moore, Sherri M.; Wheeler, Michael D.
Background Peroxisome proliferator activated receptor alpha (PPARα), a regulator of enzymes involved in β oxidation, has been reported to influence lymphocyte activation. The purpose of this study was to determine whether PPARα plays a role in T cell-mediated hepatitis induced by Concanavalin A (ConA). Methods Wild type (wt) or PPARα-deficient (PPARα−/−) mice were treated with ConA (15 mg/kg) by intravenous injection 0, 10 or 24 h prior to sacrifice and serum and tissue collection for analysis of tissue injury, cytokine response, T cell activation and characterization. Results Ten and 24 h following ConA administration, wt mice had significant liver injury as demonstrated by serum transaminase levels, inflammatory cell infiltrate, hepatocyte apoptosis, and expression of several cytokines including interleukin 4 (IL4) and interferon gamma (IFNγ). In contrast, PPARα−/− mice were protected from ConA-induced liver injury with significant reductions in serum enzyme release, greatly reduced inflammatory cell infiltrate, hepatocellular apoptosis, and IFNγ expression, despite having similar levels of hepatic T cell activation and IL4 expression. This resistance to liver injury was correlated with reduced numbers of hepatic natural killer T (NKT) cells and their in vivo responsiveness to alpha-galactosylceramide. Interestingly, adoptive transfer of either wt or PPARα−/− splenocytes reconstituted ConA liver injury and cytokine production in lymphocyte-deficient, severe combined immunodeficient mice implicating PPARα within the liver, possibly through support of IL15 expression and/or suppression of IL12 production and not the lymphocyte as the key regulator of T cell activity and ConA-induced liver injury. Conclusion Taken together, these data suggest that PPARα within the liver plays an important role in ConA-mediated liver injury through regulation of NKT cell recruitment and/or survival.
Copyright © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License, (http://creativecommons.org/licenses/by/4.0/). The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Hines, Ian N., & Kremer, Michael, & Moore, Sherri M., & Wheeler, Michael D.. (February 2018). Impaired T cell-mediated hepatitis in peroxisome proliferator activated receptor alpha (PPARα)-deficient mice. Biological Research, (51:5), p.1-16. Retrieved from http://hdl.handle.net/10342/6811
Hines, Ian N., and Kremer, Michael, and Moore, Sherri M., and Wheeler, Michael D.. "Impaired T cell-mediated hepatitis in peroxisome proliferator activated receptor alpha (PPARα)-deficient mice". Biological Research. 51:5. (1-16.), February 2018. March 28, 2020. http://hdl.handle.net/10342/6811.
Hines, Ian N. and Kremer, Michael and Moore, Sherri M. and Wheeler, Michael D., "Impaired T cell-mediated hepatitis in peroxisome proliferator activated receptor alpha (PPARα)-deficient mice," Biological Research 51, no. 5 (February 2018), http://hdl.handle.net/10342/6811 (accessed March 28, 2020).
Hines, Ian N., Kremer, Michael, Moore, Sherri M., Wheeler, Michael D.. Impaired T cell-mediated hepatitis in peroxisome proliferator activated receptor alpha (PPARα)-deficient mice. Biological Research. February 2018; 51(5) 1-16. http://hdl.handle.net/10342/6811. Accessed March 28, 2020.