Ahn Sang-Il, Kim Ji-Soo, Shin Hyeon-Myeong, Kim Ah-Yeon, Gu Gyo-Jeong, Shim Hyun-Jin, Kim Yeon Joo, Koh Kwang Oh, Mang Joo Yang, Kim Dae Young, Youn Hyung-Sun
Departments of Medical Science, College of Medical Sciences, SoonChunHyang University, Chungnam, Asan 336-745, Republic of Korea.
Department of Biomedical Laboratory Science, College of Medical Sciences, SoonChunHyang University, Chungnam, Asan 336-745, Republic of Korea.
Int Immunopharmacol. 2016 Jun;35:193-200. doi: 10.1016/j.intimp.2016.03.042. Epub 2016 Apr 16.
Toll-like receptors (TLRs) play significant roles in recognizing the pathogen-associated molecular patterns that induce innate immunity, and subsequently, acquired immunity. In general, TLRs have two downstream signaling pathways, the myeloid differential factor 88 (MyD88)-dependent and toll-interleukin-1 receptor domain-containing adapter-inducing interferon-β (TRIF)-dependent pathways, which lead to the activation of nuclear factor-kappa B (NF-κB) and interferon regulatory factor 3 (IRF3). 1-[5-methoxy-2-(2-nitrovinyl)phenyl]pyrrolidine (MNP) has been previously synthesized in our laboratory. To evaluate the therapeutic potential of MNP, its effect on signal transduction via the TLR signaling pathways was examined. MNP was shown to inhibit the activation of NF-κB and IRF3 induced by TLR agonists, as well as to inhibit the expression of cyclooxygenase-2, inducible nitric oxide synthase, and interferon inducible protein-10. MNP also inhibited the activation of NF-κB and IRF3 induced by the overexpression of downstream signaling components of the MyD88- or TRIF-dependent signaling pathways. These results suggest that MNP can modulate MyD88- and TRIF-dependent signaling pathways of TLRs, leading to decreased inflammatory gene expression.
Toll样受体（TLRs）在识别诱导先天免疫以及随后的获得性免疫的病原体相关分子模式中发挥着重要作用。一般来说，TLRs有两条下游信号通路，即髓样分化因子88（MyD88）依赖型和含Toll白细胞介素-1受体结构域的衔接蛋白诱导干扰素-β（TRIF）依赖型通路，这两条通路会导致核因子-κB（NF-κB）和干扰素调节因子3（IRF3）的激活。1-[5-甲氧基-2-（2-硝基乙烯基）苯基]吡咯烷（MNP）此前已在我们实验室合成。为了评估MNP的治疗潜力，研究了其对通过TLR信号通路进行的信号转导的影响。结果表明，MNP可抑制TLR激动剂诱导的NF-κB和IRF3的激活，以及抑制环氧合酶-2、诱导型一氧化氮合酶和干扰素诱导蛋白-10的表达。MNP还抑制了由MyD88或TRIF依赖型信号通路的下游信号成分过表达所诱导的NF-κB和IRF3的激活。这些结果表明，MNP可以调节TLRs的MyD88和TRIF依赖型信号通路，从而导致炎症基因表达降低。
