Pioglitazone Inhibits Toll-Like Receptor Expression and Activity in Human Monocytes and db/db Mice
Pioglitazone Inhibits Toll-Like Receptor Expression and Activity in Human Monocytes and db/db Mice
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DOI：
10.1210/en.2008-1757
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发表时间：
2009-08-01
期刊：
影响因子：
4.8
通讯作者：
Jialal, Ishwarlal
中科院分区：
文献类型：
--
作者：
Dasu, Mohan R.;Park, Samuel;Jialal, Ishwarlal
Toll样受体是内源性损伤信号的关键先天免疫感受器，在糖尿病、动脉粥样硬化等炎症性疾病中发挥重要作用。吡格列酮(PIO)是一种过氧化物酶体增殖物激活受体(PPAR)-γ激动剂，已被报道为抗炎药。因此，在本研究中，我们利用流式细胞术和实时荧光定量RT-PCR检测了PIO对Pam3CSK4(Pam；TLR2配体)和纯化的脂多糖(LPS；TLR4配体)刺激的人单核细胞TLR2和TLR4表达的抗炎作用。从健康志愿者中分离单核细胞，用PIO(1MU M)处理，然后用PAM(170 ng/ml)和内毒素(160 ng/ml)刺激。Pio能显著降低Pam和LPS诱导的TLR2(-56%)和TLR4(-78%)的表达(P<；0.05)。此外，与对照组相比，PIO还降低了TLR配体诱导的核因子-kappaB(-63%)、IL-1β(-50%)、IL-6(-52%)、单核细胞趋化蛋白-1(-83%)和肿瘤坏死因子-α(-87%)的活性。接下来，与赋形剂对照组(P<；0.001)相比，经PIO处理的db/db小鼠(n=6/组)的腹膜巨噬细胞中TLR2(-60%)和TLR4(-45%)的表达降低，MyD88依赖的信号转导和核因子-kappaB的激活也相应减少。数据表明，PIO可抑制PAM和LPS诱导的人单核细胞和db/db小鼠TLR2和TLR4的表达。因此，我们定义了PIO诱导抗炎作用的新途径。(内分泌学150：3457-3464,2009)
Toll-like receptors (TLRs) are key innate immune sensors of endogenous damage signals and play an important role in inflammatory diseases like diabetes and atherosclerosis. Pioglitazone (PIO), a peroxisome proliferator-activated receptor (PPAR)-gamma agonist, has been reported to be an antiinflammatory agent. Thus, in the present study, we examined the antiinflammatory effects of PIO on TLR2 and TLR4 expression in human monocytes exposed to Pam3CSK4 (Pam; TLR2 ligand) and purified lipopolysaccharide (LPS; TLR4 ligand) using flow cytometry and real-time RT-PCR. Monocytes were isolated from healthy human volunteers and pretreated with PIO (1 mu M) followed by Pam (170 ng/ml) and LPS (160 ng/ml) challenge. PIO significantly decreased Pam- and LPS-induced TLR2 (-56%) and TLR4 (-78%) expression (P < 0.05). In addition, PIO decreased TLR ligand-induced nuclear factor-kappa B activity (-63%), IL-1 beta (-50%), IL-6 (-52%), monocyte chemoattractant protein-1(-83%), and TNF-alpha (-87%) compared with control. Next, PIO-treated db/db mice (n=6/ group) showed decreased TLR2 (-60%) and TLR4 (-45%) expression in peritoneal macrophages compared with vehicle control mice (P < 0.001) with associated decrease in MyD88-dependent signaling and nuclear factor-kappa B activation. Data suggest that Pam- and LPS-induced TLR2 and TLR4 expression are inhibited by PIO in human monocytes and db/db mice. Thus, we define a novel pathway by which PIO could induce antiinflammatory effects. (Endocrinology 150: 3457-3464, 2009)