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

  • Biol Res. 2018 Feb 15;51(1):5. doi: 10.1186/s40659-018-0153-z.
Ian N Hines  1  2 ,  Michael Kremer  3  4 ,  Sherri M Moore  5 ,  Michael D Wheeler  5  4
Affiliations
  • 1. Department of Nutrition Science, College of Allied Health Sciences, East Carolina University, Health Sciences Bldg. Room 4165F, Greenville, NC, 27834, USA. [email protected].
  • 2. Department of Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA. [email protected].
  • 3. Department of General Surgery, University of Ulm, Ulm, Germany.
  • 4. Department of Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA.
  • 5. Department of Nutrition Science, College of Allied Health Sciences, East Carolina University, Health Sciences Bldg. Room 4165F, Greenville, NC, 27834, USA.
PMID: 29448959 DOI: 10.1186/s40659-018-0153-z
Abstract

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.

Keywords
Cytokines; Inflammation; Interferon gamma; T helper phenotype.
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