Waiskopf Nir, Ofek Keren, Gilboa-Geffen Adi, Bekenstein Uriya, Bahat Assaf, Bennett Estelle R, Podoly Erez, Livnah Oded, Hartmann Gunther, Soreq Hermona
Department of Biological Chemistry and The Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel.
J Mol Neurosci. 2014 Jul;53(3):306-15. doi: 10.1007/s12031-013-0174-6. Epub 2013 Nov 21.
Selective serotonin reuptake inhibitors (SSRIs) show anti-inflammatory effects, suggesting a possible interaction with both Toll-like-receptor 4 (TLR4) responses and cholinergic signaling through as yet unclear molecular mechanism(s). Our results of structural modeling support the concept that the antidepressant fluoxetine physically interacts with the TLR4-myeloid differentiation factor-2 complex at the same site as bacterial lipopolysaccharide (LPS). We also demonstrate reduced LPS-induced pro-inflammatory interleukin-6 and tumor necrosis factor alpha in human peripheral blood mononuclear cells preincubated with fluoxetine. Furthermore, we show that fluoxetine intercepts the LPS-induced decreases in intracellular acetylcholinesterase (AChE-S) and that AChE-S interacts with the nuclear factor kappa B (NFκB)-activating intracellular receptor for activated C kinase 1 (RACK1). This interaction may prevent NFκB activation by residual RACK1 and its interacting protein kinase PKCβII. Our findings attribute the anti-inflammatory properties of SSRI to surface membrane interference with leukocyte TLR4 activation accompanied by intracellular limitation of pathogen-inducible changes in AChE-S, RACK1, and PKCβII.
选择性5-羟色胺再摄取抑制剂（SSRI）具有抗炎作用，这表明其可能通过目前尚不清楚的分子机制与Toll样受体4（TLR4）反应及胆碱能信号传导相互作用。我们的结构建模结果支持这样一种概念，即抗抑郁药氟西汀与细菌脂多糖（LPS）在同一部位与TLR4-髓样分化因子2复合物发生物理相互作用。我们还证明，在用氟西汀预孵育的人外周血单核细胞中，LPS诱导的促炎白细胞介素-6和肿瘤坏死因子α减少。此外，我们表明氟西汀可阻断LPS诱导的细胞内乙酰胆碱酯酶（AChE-S）降低，并且AChE-S与核因子κB（NFκB）激活的细胞内活化C激酶1受体（RACK1）相互作用。这种相互作用可能通过残余的RACK1及其相互作用的蛋白激酶PKCβII来阻止NFκB的激活。我们的研究结果将SSRI的抗炎特性归因于对白细胞TLR4激活的表面膜干扰，同时伴有对病原体诱导的AChE-S、RACK1和PKCβII细胞内变化的限制。
