α4β2 Nicotinic Receptors Partially Mediate Anti-Inflammatory Effects through Janus Kinase 2-Signal Transducer and Activator of Transcription 3 but Not Calcium or cAMP Signaling
α4β2 Nicotinic Receptors Partially Mediate Anti-Inflammatory Effects through Janus Kinase 2-Signal Transducer and Activator of Transcription 3 but Not Calcium or cAMP Signaling
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DOI：
10.1124/mol.110.066381
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发表时间：
2011-01-01
影响因子：
3.6
通讯作者：
Loring, Ralph H.
中科院分区：
文献类型：
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作者：
Hosur, Vishnu;Loring, Ralph H.
尽管有证据表明吸烟可以预防神经系统疾病，但具体的尼古丁受体亚型是如何以及是否参与其中尚不清楚。我们以前报道过，尼古丁抑制构成核因子κ B （nf - κ B）活性，从而抑制α 4 β 2尼古丁受体稳定转染的SHEP1细胞中促炎细胞因子（PIC）的产生。在这里，我们报道了尼古丁预处理对脂多糖（LPS）刺激的SHEP1细胞的抗炎作用。尼古丁（100-300 nM，吸烟者血液中发现的浓度）阻断lps诱导的NF-kappa B易位和PICs白细胞介素(IL)-1 β和IL-6的产生，但仅部分阻断核因子-kappa B α (I kappa B α)磷酸化抑制剂。这些作用仅在转染了α 4 β 2受体的细胞中出现，而在野生型细胞中没有。细胞可透性钙螯合剂1,2-二（2-氨基苯氧基）乙烷-N，N，N‘，N’-四乙酸-乙酰氧基甲酯、腺苷酸环化酶刺激剂forskolin和特异性蛋白激酶a （PKA）抑制剂PKI 14-22-酰胺未能阻断尼古丁对lps诱导的NF-kappa B易位和I -kappa B α磷酸化的影响。然而，尼古丁对NF-kappa B活性的影响被高度特异性的janus kinase 2 （JAK2）抑制剂α -氰基-（3,4-二羟基）- n -苄基肉桂酸（AG-490）和转录信号转导和激活因子3 （STAT3）抑制剂2-羟基-4-[[[[（4-甲基苯基）磺酰基[氧]乙酰基]氨基]苯甲酸（NSC74859）显著阻断。这些发现揭示了一个不依赖于钙和camp - pka的信号级联，并提示JAK2-STAT3转导在α 4 β 2介导的脂多糖诱导炎症的衰减中起作用。因此，尼古丁的抗炎作用可能是通过α 4 β 2受体介导的，α 4 β 2受体是中枢神经系统中尼古丁的主要高亲和力结合位点，此外还有更完善的α 7受体。
Despite evidence that smoking confers protection against neurological disorders, how and whether specific nicotinic receptor subtypes are involved is unknown. We reported previously that nicotine suppresses constitutive nuclear factor kappa B (NF-kappa B) activity and thereby proinflammatory cytokine (PIC) production in SHEP1 cells stably transfected with alpha 4 beta 2 nicotinic receptors. Here, we report the anti-inflammatory effects of nicotine pretreatment in lipopolysaccharide (LPS)-stimulated SHEP1 cells. Nicotine (100-300 nM, concentrations found in smoker's blood) blocked LPS-induced NF-kappa B translocation and production of PICs interleukin (IL)-1 beta and IL-6 but only partially blocked inhibitor of nuclear factor-kappa B alpha (I kappa B alpha) phosphorylation. These effects were exclusively in cells transfected with alpha 4 beta 2 receptors but not in wild types. The cell-permeable calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester, the adenylate cyclase stimulant forskolin, and a specific protein kinase A (PKA) inhibitor PKI 14-22-amide failed to block the effect of nicotine on LPS-induced NF-kappa B translocation and I kappa B alpha phosphorylation. However, the effects of nicotine on NF-kappa B activity were significantly blocked by the highly specific janus kinase 2 (JAK2) inhibitor alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide (AG-490) and the signal transducer and activator of transcription 3 (STAT3) inhibitor 2-hydroxy-4-[[[[(4-methylphenyl)sulfonyl]oxy]acetyl]amino]benzoic acid (NSC74859). These findings reveal a calcium-and cAMP-PKA-independent signaling cascade and suggest a role for JAK2-STAT3 transduction in alpha 4 beta 2-mediated attenuation of LPS-induced inflammation. Anti-inflammatory effects of nicotine may therefore be mediated through alpha 4 beta 2 receptors, the predominant high-affinity binding sites for nicotine in the central nervous system, in addition to the better-established alpha 7 receptors.