Abscisic Acid Regulates Inflammation via Ligand-binding Domain-independent Activation of Peroxisome Proliferator-activated Receptor gamma

作者：Bassaganya Riera Josep^*; Guri Amir J; Lu Pinyi; Climent Montse; Carbo Adria; Sobral Bruno W; Horne William T; Lewis Stephanie N; Bevan David R; Hontecillas Raquel

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286(4): 2504-2516.

DOI：10.1074/jbc.M110.160077

Abscisic acid (ABA) has shown efficacy in the treatment of diabetes and inflammation; however, its molecular targets and the mechanisms of action underlying its immunomodulatory effects remain unclear. This study investigates the role of peroxisome proliferator-activated receptor gamma (PPAR gamma) and lanthionine synthetase C-like 2 (LANCL2) as molecular targets for ABA. We demonstrate that ABA increases PPAR gamma reporter activity in RAW 264.7 macrophages and increases ppar gamma expression in vivo, although it does not bind to the ligand-binding domain of PPAR gamma. LANCL2 knockdown studies provide evidence that ABA-mediated activation of macrophage PPAR gamma is dependent on lancl2 expression. Consistent with the association of LANCL2 with G proteins, we provide evidence that ABA increases cAMP accumulation in immune cells. ABA suppresses LPS-induced prostaglandin E(2) and MCP-1 production via a PPAR gamma-dependent mechanism possibly involving activation of PPAR gamma and suppression of NF-kappa B and nuclear factor of activated T cells. LPS challenge studies in PPAR gamma-expressing and immune cell-specific PPAR gamma null mice demonstrate that ABA down-regulates toll-like receptor 4 expression in macrophages and T cells in vivo through a PPAR gamma-dependent mechanism. Global transcriptomic profiling and confirmatory quantitative RT-PCR suggest novel candidate targets and demonstrate that ABA treatment mitigates the effect of LPS on the expression of genes involved in inflammation, metabolism, and cell signaling, in part, through PPAR gamma. In conclusion, ABA decreases LPS-mediated inflammation and regulates innate immune responses through a bifurcating pathway involving LANCL2 and an alternative, ligand-binding domain-independent mechanism of PPAR gamma activation.

• 出版日期2011-1-28