Retinoic acid alleviates Con A‐induced hepatitis and differentially regulates effector production in NKT cells

Abstract

IntroductionLiver damage induced by various agents, such as viral infection, results in serious problems accompanied by an excessive immune response [1]. Uncontrolled severe responses in the liver by immune cells are observed in diverse animal models, including Con A-induced hepatitis. Following the administration of Con A, T cells, granulocytes, and Kupffer cells infiltrate into the liver, resulting in the death of hepatocytes [2][3][4]. NKT cells are responsible Correspondence: Prof. Chang-Yuil Kang e-mail: cykang@snu.ac.kr for liver injury in this model [5][6][7][8][9][10]. NKT cells are a distinct T-cell subset with an invariant T-cell receptor (TCR) that recognizes glycolipids loaded on the cell-surface protein CD1d, and they rapidly secrete cytokines upon stimulation [11][12][13][14]. In Con A-induced liver injury, inflammatory cytokines, such as IFN-γ, TNF-α, and IL-4, from NKT cells are pathogenic [5,7,9,10]. In addition, a specific ligand of NKT cells, α-GalCer, can induce liver injury mediated by FasL and TNF-α rather than . Although NKT cells are critical to induce both Con A-and α-GalCer-induced liver injury, their pathologic mechanisms are different from each other.www.eji-journal.eu1686 Kyoo-A Lee et al. Eur. J. Immunol. 2012. 42: 1685-1694 Retinoic acid (RA), an active metabolite of vitamin A, regulates various diseases through anti-tumor and anti-inflammatory effects [18,19]. RA is associated with anti-inflammatory effects in diverse diseases [20]. RA also enhances T-cell effector responses and is critical in vaccine responses [21][22][23][24][25]. These contradictory findings imply that the exact physiological function of RA remains to be discovered. RA promotes the proliferation and activation of NKT cells indirectly in vitro by increasing CD1d expression in APCs [26][27][28]. However, the direct effects of RA on NKT cells and NKT cell-dependent diseases in vivo have not been examined. In the current study, we observed that RA differentially regulates NKT cell-mediated hepatitis and cytokine production by NKT cells. Our results suggest the selective regulatory effects and the therapeutic potential of RA in NKT cell-dependent diseases. Results RA regulates Con A-induced hepatitis and differentially regulates cytokine levels in serumTo determine the effect of RA itself, we injected RA directly into normal mice, and liver injury was induced by injecting Con A. The RA-treated group had a 100% survival rate, whereas the entire control group succumbed to the lethal dose (30 mg/kg) several hours after the Con A injection (Fig. 1A). In addition, when the ALT activity was measured in animals with nonlethal (20 mg/kg) Con A-induced hepatitis, significantly less ALT activity was observed in the RA-treated group (Fig. 1B). And also, liver histology showed massive necrosis in vehicle-treated mice, but in RA-treated mice, the liver tissue maintained the structure (Fig. 1C). Treatment with disulfiram, a blocking agent of RALDH that synthesizes RA, aggravated the survival rate and serum ALT activity, indicat...

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