Impaired T cell-mediated hepatitis in peroxisome proliferator activated receptor alpha (PPARα)-deficient mice
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 hep...
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Sociedad de Biología de Chile
2018
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oai:scielo:S0716-976020180001002042018-03-09Impaired T cell-mediated hepatitis in peroxisome proliferator activated receptor alpha (PPARα)-deficient miceHines,Ian N.Kremer,MichaelMoore,Sherri M.Wheeler,Michael D. Inflammation Cytokines T helper phenotype Interferon gamma 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.info:eu-repo/semantics/openAccessSociedad de Biología de ChileBiological Research v.51 20182018-01-01text/htmlhttp://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0716-97602018000100204en10.1186/s40659-018-0153-z |
| institution |
Scielo Chile |
| collection |
Scielo Chile |
| language |
English |
| topic |
Inflammation Cytokines T helper phenotype Interferon gamma |
| spellingShingle |
Inflammation Cytokines T helper phenotype Interferon gamma 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 |
| description |
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. |
| author |
Hines,Ian N. Kremer,Michael Moore,Sherri M. Wheeler,Michael D. |
| author_facet |
Hines,Ian N. Kremer,Michael Moore,Sherri M. Wheeler,Michael D. |
| author_sort |
Hines,Ian N. |
| title |
Impaired T cell-mediated hepatitis in peroxisome proliferator activated receptor alpha (PPARα)-deficient mice |
| title_short |
Impaired T cell-mediated hepatitis in peroxisome proliferator activated receptor alpha (PPARα)-deficient mice |
| title_full |
Impaired T cell-mediated hepatitis in peroxisome proliferator activated receptor alpha (PPARα)-deficient mice |
| title_fullStr |
Impaired T cell-mediated hepatitis in peroxisome proliferator activated receptor alpha (PPARα)-deficient mice |
| title_full_unstemmed |
Impaired T cell-mediated hepatitis in peroxisome proliferator activated receptor alpha (PPARα)-deficient mice |
| title_sort |
impaired t cell-mediated hepatitis in peroxisome proliferator activated receptor alpha (pparα)-deficient mice |
| publisher |
Sociedad de Biología de Chile |
| publishDate |
2018 |
| url |
http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0716-97602018000100204 |
| work_keys_str_mv |
AT hinesiann impairedtcellmediatedhepatitisinperoxisomeproliferatoractivatedreceptoralphappar945deficientmice AT kremermichael impairedtcellmediatedhepatitisinperoxisomeproliferatoractivatedreceptoralphappar945deficientmice AT mooresherrim impairedtcellmediatedhepatitisinperoxisomeproliferatoractivatedreceptoralphappar945deficientmice AT wheelermichaeld impairedtcellmediatedhepatitisinperoxisomeproliferatoractivatedreceptoralphappar945deficientmice |
| _version_ |
1718441569017659392 |