Abscisic Acid Regulates Inflammation via Ligand-binding Domain-independent Activation of Peroxisome Proliferator-activated Receptor γ
Abscisic Acid Regulates Inflammation via Ligand-binding Domain-independent Activation of Peroxisome Proliferator-activated Receptor γ
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DOI：
10.1074/jbc.m110.160077
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发表时间：
2011-01-28
影响因子：
4.8
通讯作者：
Hontecillas, Raquel
中科院分区：
文献类型：
--
作者：
Bassaganya-Riera, Josep;Guri, Amir J.;Hontecillas, Raquel
脱落酸 (ABA) 在治疗糖尿病和炎症方面显示出功效；然而，其免疫调节作用的分子靶点和作用机制仍不清楚。本研究探讨了过氧化物酶体增殖物激活受体 γ (PPAR γ) 和羊毛硫氨酸合成酶 C 样 2 (LANCL2) 作为 ABA 分子靶标的作用。我们证明 ABA 增加了 RAW 264.7 巨噬细胞中 PPAR gamma 报告基因的活性，并增加了体内 ppar gamma 的表达，尽管它不与 PPAR gamma 的配体结合域结合。 LANCL2 敲低研究提供证据表明 ABA 介导的巨噬细胞 PPAR gamma 激活依赖于 lancl2 表达。与 LANCL2 与 G 蛋白的关联一致，我们提供了 ABA 增加免疫细胞中 cAMP 积累的证据。 ABA 通过 PPAR γ 依赖性机制抑制 LPS 诱导的前列腺素 E-2 和 MCP-1 的产生，该机制可能涉及 PPAR γ 的激活以及活化 T 细胞的 NF-κ B 和核因子的抑制。在表达 PPAR γ 和免疫细胞特异性 PPAR γ 无效小鼠中进行的 LPS 攻击研究表明，ABA 通过 PPAR γ 依赖性机制下调体内巨噬细胞和 T 细胞中 Toll 样受体 4 的表达。整体转录组分析和验证性定量 RT-PCR 提出了新的候选靶标，并证明 ABA 治疗部分通过 PPAR gamma 减轻了 LPS 对涉及炎症、代谢和细胞信号传导的基因表达的影响。总之，ABA 通过涉及 LANCL2 的分叉途径和另一种不依赖于配体结合域的 PPAR γ 激活机制，减少 LPS 介导的炎症并调节先天免疫反应。
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.