Impaired T cell-mediated hepatitis in peroxisome proliferator activated receptor alpha (PPARa)-deficient mice

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Ian N. Hines (Creator)

Michael Kremer (Creator)

Sherri M. Moore (Creator)

Michael D. Wheeler (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Background\r\nPeroxisome proliferator activated receptor alpha (PPARa), a regulator of enzymes involved in ß oxidation, has been reported to influence lymphocyte activation. The purpose of this study was to determine whether PPARa plays a role in T cell-mediated hepatitis induced by Concanavalin A (ConA).\r\n\r\nMethods\r\nWild type (wt) or PPARa-deficient (PPARa-/-) 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.\r\n\r\nResults\r\nTen 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 (IFN?). In contrast, PPARa-/- mice were protected from ConA-induced liver injury with significant reductions in serum enzyme release, greatly reduced inflammatory cell infiltrate, hepatocellular apoptosis, and IFN? 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 PPARa-/- splenocytes reconstituted ConA liver injury and cytokine production in lymphocyte-deficient, severe combined immunodeficient mice implicating PPARa 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.\r\n\r\nConclusion\r\nTaken together, these data suggest that PPARa within the liver plays an important role in ConA-mediated liver injury through regulation of NKT cell recruitment and/or survival.

Additional Information

Publication

Other

Hines, I. N., Kremer, M., Moore, S. M., & Wheeler, M. D. (2018). Impaired T cell-mediated hepatitis in peroxisome proliferator activated receptor alpha (PPARa)-deficient mice. Biological Research, 51(1), 5. https://doi.org/10.1186/s40659-018-0153-z

Language: English

Date: 2023

Subjects

Inflammation;Cytokines;T helper phenotype;Interferon gamma

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