Inhibition of p38/Mk2 signaling pathway improves the anti-inflammatory effect of WIN55 on mouse experimental colitis
Inhibition of p38/Mk2 signaling pathway improves the anti-inflammatory effect of WIN55 on mouse experimental colitis
复制标题
抑制p38/Mk2信号通路提高WIN55对小鼠实验性结肠炎的抗炎作用
DOI：
10.1038/labinvest.2012.177
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发表时间：
2013-03-01
影响因子：
5
通讯作者：
Storr, Martin
中科院分区：
文献类型：
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作者：
Li, Yu Y.;Yuece, Birol;Storr, Martin
P38/MK2(丝裂原活化蛋白激酶，MAPK)活化的蛋白激酶-2，又称MAKAP激酶-2，是丝裂原活化蛋白激酶(MAPKs)家族的成员，直接或间接参与炎症反应。WIN55,212-2(WIN55)是一种人工合成的非选择性大麻素受体激动剂，具有显著的抗炎作用。本研究旨在探讨WIN55和p38/Mk2信号通路在葡聚糖硫酸钠(DSS)诱导的小鼠结肠炎中的作用及其抗炎机制。C57BLMK2基因纯合缺失(MK2DSS)小鼠和野生型小鼠用4%−/−溶液代替饮水7d，诱发结肠炎。DSS治疗的小鼠出现便血、体重减轻和结肠粘膜上可见的多发性出血溃疡。结肠组织中肿瘤坏死因子-α和白介素6的表达水平以及p38及其磷酸化形式(p-p38)的蛋白表达水平均上调。α、IL-6、细胞因子诱导的中性粒细胞趋化因子-1、单核细胞趋化蛋白-1及肺组织髓过氧化物酶活性均升高，而MK2-−/−小鼠上述变化较轻。在WIN55干预后，MK2−/−小鼠比野生型小鼠从诱导的结肠炎中恢复得更快、更好。结果表明，小鼠MK2纯合子缺失阻碍了DSS诱导的实验性结肠炎，证实了p38/MK2参与了这一炎症反应。WIN55保护小鼠免受DSS诱导的结肠炎，特别是当p38/Mk2途径被阻断时，这意味着CB系统的激活，以及p38/Mk2途径的阻断，是治疗结肠炎的潜在药物靶点。
P38/Mk2 (mitogen-activated protein kinase (MAPK)-activated protein kinase-2, also known as MAKAP kinase-2) is a member of the mitogen-activated protein kinases (MAPKs) family, and participates in inflammatory responses directly or indirectly. WIN55, 212-2 (WIN55) is a synthetic non-selective agonist of cannabinoid (CB) receptors with remarkable anti-inflammatory properties. This study was to explore the roles of WIN55 and p38/Mk2 signaling pathway in dextran sodium sulfate (DSS)-induced mouse colitis and ascertain their anti-inflammatory mechanisms. Colitis was induced in C57BL Mk2 gene homozygous deletion (Mk2−/−) and wild-type mice by replacing the drinking water with 4% DSS solution for 7 days. DSS-treated mice developed bloody stool, weight loss, and eye-visible multiple bleeding ulcers on colon mucosa. The mRNA expressions levels of TNF-α and IL-6, as well as the protein levels of p38 and its phosphorylated form (p-p38), were upregulated in the colon. The plasma levels of TNF-α, IL-6, cytokine-induced neutrophil chemoattractant-1 (CINC-1), monocyte chemoattractant protein-1 (MCP-1), and lung myeloperoxidase (MPO) activities were raised; however, all these changes were less severe in Mk2−/− mice. After WIN55 intervention, the Mk2−/− mice recovered faster and better from the induced colitis than their wild-type counterparts. The results indicate that the Mk2 homozygous deletion in mice impedes the induction of experimental colitis by DSS, confirming the notion that p38/Mk2 is involved in this inflammatory response. WIN55 protects mice against DSS-induced colitis, in particular when the p38/Mk2 pathway is obstructed, implying that the activation of CB system, together with blocking of p38/Mk2 pathway, serves as a potential drug target for colitis treatment.