Department of Pharmaceutical Science, Northeastern University, Boston, Massachusetts 02115, USA.
Mol Pharmacol. 2011 Jan;79(1):167-74. doi: 10.1124/mol.110.066381. Epub 2010 Oct 13.
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 κB (NF-κB) activity and thereby proinflammatory cytokine (PIC) production in SHEP1 cells stably transfected with α4β2 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-κB translocation and production of PICs interleukin (IL)-1β and IL-6 but only partially blocked inhibitor of nuclear factor-κBα (IκBα) phosphorylation. These effects were exclusively in cells transfected with α4β2 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-κB translocation and IκBα phosphorylation. However, the effects of nicotine on NF-κB activity were significantly blocked by the highly specific janus kinase 2 (JAK2) inhibitor α-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 α4β2-mediated attenuation of LPS-induced inflammation. Anti-inflammatory effects of nicotine may therefore be mediated through α4β2 receptors, the predominant high-affinity binding sites for nicotine in the central nervous system, in addition to the better-established α7 receptors.
尽管有证据表明吸烟能预防神经紊乱，但具体的烟碱型乙酰胆碱受体亚型如何以及是否参与其中尚不清楚。我们之前曾报道过，尼古丁能抑制稳定转染α4β2 型烟碱受体的 SHEP1 细胞中组成型核因子κB（NF-κB）的活性，从而抑制促炎细胞因子（PIC）的产生。在此，我们报告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，吸烟者血液中的浓度）阻断 LPS 诱导的 NF-κB 易位和 PICs 白细胞介素（IL）-1β和 IL-6 的产生，但仅部分阻断核因子-κBα（IκBα）磷酸化。这些作用仅在转染有α4β2 受体的细胞中出现，而在野生型细胞中则没有。细胞通透性钙螯合剂 1,2-双（2-氨基苯氧基）乙烷-N,N,N',N'-四乙酸-乙氧甲酯、腺苷酸环化酶刺激剂 forskolin 和特定的蛋白激酶 A（PKA）抑制剂 PKI 14-22-酰胺都不能阻断尼古丁对 LPS 诱导的 NF-κB 易位和 IκBα磷酸化的作用。然而，尼古丁对 NF-κB 活性的作用被高度特异性的 Janus 激酶 2（JAK2）抑制剂 α-氰基-（3,4-二羟基）-N-苄基肉桂酰胺（AG-490）和信号转导和转录激活因子 3（STAT3）抑制剂 2-羟基-4-[[[[（4-甲基苯基）磺酰基]氧基]乙酰基]氨基]-苯甲酸（NSC74859）显著阻断。这些发现揭示了一个钙和 cAMP-PKA 非依赖性信号级联，表明 JAK2-STAT3 转导在 α4β2 介导的 LPS 诱导炎症抑制中起作用。因此，尼古丁的抗炎作用可能是通过α4β2 受体介导的，α4β2 受体是中枢神经系统中尼古丁的主要高亲和力结合位点，此外还有更好地建立起来的α7 受体。
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