Shalini V, Jayalekshmi Ananthasankaran, Helen A
Department of Biochemistry, University of Kerala Kariavattom Campus, Thiruvananthpuram, Kerala 695581, India.
Chemical Sciences & Technology Division, National Institute for Interdisciplinary Science and Technology (NIIST), CSIR, Industrial Estate P.O., Thiruvananthapuram, Kerala 695019, India.
Mol Immunol. 2015 Aug;66(2):229-39. doi: 10.1016/j.molimm.2015.03.004. Epub 2015 Mar 31.
Njavara is an indigenous medicinal rice variety traditionally used in Ayurvedic system of medicine practiced in Kerala, India. Tricin is a bioflavonoid present in significantly higher levels in rice bran of Njavara. Present study attempted to identify the molecular target of tricin in TLR mediated signaling pathways by using lipopolysaccharide (LPS) induced human peripheral blood mononuclear cells (hPBMCs) and carrageenan induced paw edema in rats as experimental models. Tricin acted upstream in the activation of inflammation cascade by interfering with TLR4 activation, preferably by blocking the LPS induced activation of TLR4, MYD88 and TRIF proteins in hPBMCs. Subsequently, tricin significantly blocked the activation of downstream kinases like p38MAPK, JNK1/2 and IRF3. Thus the inhibitory effect of tricin on NF-κB and IRF3 together confirms the specific inhibition of both MYD88 dependent and TRIF dependent pathways. Tricin treatment also inhibited the pro-inflammatory effect of LPS by blocking the TLR4 signaling mediated activation of cytosolic phospholipase A2 (cPLA2), which is confirmed by specific inhibition of COX-2. Results demonstrated that in addition to NF-κB, tricin can prevent the activation of STAT proteins by significantly inhibiting the activation of both STAT1 and STAT3 via the down regulation of upstream phosphorylating enzymes like JAK1 and JAK2. The protective anti-inflammatory effect of tricin was also confirmed by in vivo experiments. Thus, this study provides strong evidence that tricin exerts its anti-inflammatory effect via a mechanism involving the TLR4/NF-κB/STAT signaling cascade.
香稻是印度喀拉拉邦传统阿育吠陀医学体系中使用的一种本土药用稻品种。小麦黄素是一种生物类黄酮，在香稻的米糠中含量显著更高。本研究试图以脂多糖（LPS）诱导的人外周血单核细胞（hPBMCs）和角叉菜胶诱导的大鼠足爪肿胀为实验模型，确定小麦黄素在TLR介导的信号通路中的分子靶点。小麦黄素通过干扰TLR4激活在炎症级联反应的激活中起上游作用，优选通过阻断hPBMCs中LPS诱导的TLR4、MYD88和TRIF蛋白的激活。随后，小麦黄素显著阻断了下游激酶如p38MAPK、JNK1/2和IRF3的激活。因此，小麦黄素对NF-κB和IRF3的抑制作用共同证实了对MYD88依赖性和TRIF依赖性途径的特异性抑制。小麦黄素处理还通过阻断TLR4信号介导的胞质磷脂酶A2（cPLA2）的激活来抑制LPS的促炎作用，这通过COX-2的特异性抑制得到证实。结果表明，除了NF-κB外，小麦黄素还可以通过下调上游磷酸化酶如JAK1和JAK2的激活，显著抑制STAT1和STAT3的激活，从而阻止STAT蛋白的激活。小麦黄素的保护性抗炎作用也在体内实验中得到证实。因此，本研究提供了有力证据，表明小麦黄素通过涉及TLR4/NF-κB/STAT信号级联反应的机制发挥其抗炎作用。
