MECHANISM OF CIGARETTE SMOKE-INDUCED IMMUNOSUPPRESSION

流行病学研究表明，长期吸入香烟烟雾(SM)会增加患癌症、心脏病、呼吸道感染和包括艾滋病在内的其他感染的风险。艾滋病痴呆症，以及艾滋病毒-1从母亲传给后代。我们和其他人已经证明SM抑制免疫系统，并假设SM的许多健康后果是由于其对免疫系统的影响而产生的，并且SM的许多健康后果是由其对免疫系统的影响引起的。尼古丁(NT)是SM中最重要的药理活性物质，我们的实验室首次证明长期暴露于NT会引起与SM类似的免疫抑制，并将T细胞滞留在细胞周期的G0/G1期。最近的数据表明，长期接触NT虽然具有抗炎作用，但会增加甲型流感病毒和酵母样真菌--新生隐球菌的复制和/或传播。此外，虽然NT在体外影响一些T细胞参数，但在体内的许多作用可能主要是通过中枢神经系统介导的。慢性SM或NT的免疫抑制与T淋巴细胞抗原介导的信号转导功能受损有关，从而导致T细胞无能。我们的初步结果表明，这些无能T细胞表现出蛋白酪氨酸激酶(PTKs)的内在激活，包括IL-2在内的细胞因子产生减少，有趣的是，耗尽了包括IL-2在内的对三磷酸肌醇(IP3)敏感的细胞内钙离子，有趣的是，耗尽了对三磷酸肌醇(IP3)敏感的细胞内钙存储。这些储存对T细胞的功能至关重要，包括抗原/有丝分裂原诱导的增殖和转录因子向细胞核的运输。我们的初步结果表明，在NT处理的动物的T细胞中，发现了一种与T细胞抗原受体(TCR)和烟碱型乙酰胆碱受体(NAChRs)相关的类似于Src的PTK-Fyn。有趣的是，来自感染了小鼠艾滋病病毒的小鼠的无能T细胞激活了Fyn。基于这些数据，我们假设，一个结构性的活性Fyn，通过耗尽对IP3敏感的钙离子储存，影响转录因子从细胞质向细胞核的迁移。此外，NT特异性地激活与nAChRs相关的Fyn，导致T细胞激活的“部分”状态，从而导致T细胞无能。这些研究将有助于阐明滥用神经和免疫活性药物进行免疫调节的分子机制。此外，这一结果可能为T细胞耐受和神经免疫相互作用的机制提供深入的认识。

Epidemiological studies suggest that chronic inhalation of cigarette smoke (SM) is associated with increased risk of cancer, heart disease, respiratory infections, and other infections including AIDS. AIDS dementia complex, and transmission of HIV-1 from mother to the offspring. We and others have shown that SM suppresses the immune system, and it has been postulated that many health consequences of SM result from its effects on the immune system, and it has been postulated that many health consequences of SM result from its effects on the immune system. Nicotine (NT) is the most important pharmacologically active substance in SM, and our laboratory was the first to demonstrate that chronic exposure to NT causes immunosuppression similar to SM and arrests T cells in the G0/G1 phase of the cell cycle. More recent data indicate that chronic exposure to NT, although anti-inflammatory, increases the replication and/or dissemination of the influenza A virus and the yeast-like fungus, Cryptococcus neoformans. In addition, while in vitro NT affects some T cell parameters, many in vivo effects of NT may be primarily mediated through the CNS. Immunosuppression by chronic SM or NT is causally related to the impairment of antigen-mediated signaling in T lymphocytes, leading to T cell anergy. Our preliminary results indicate that these anergic T cells exhibit intrinsic activation of protein tyrosine kinases (PTKs), decreased cytokine production including IL-2, and, interestingly, depleted inositol-1,4,5-triphosphate (IP3)- sensitive intracellular Ca2+ including IL-2, and, interestingly, depleted inositol-1/4/5-trisphosphate (IP3)-sensitive intracellular Ca2+ stores. These stores are critical for T-cell function, including antigen/mitogen- induced proliferation and the transport of transcription factors into the nucleus. Our preliminary results suggest that Fyn, a Src-like PTK found in association with T cell antigen receptors (TCRs) and nicotinic acetylcholine receptor (nAChRs), is constitutively activated in T cells from NT-treatment animals. Interestingly, anergic T cells from mice infected with murine AIDS virus have activated Fyn. Based on these data, we hypothesize that a constitutively active Fyn, through depletion of IP3- sensitive Ca2+ stores, affects the emigration of transcription factors from the cytoplasm to the nucleus. Furthermore, NT specifically activates the Fyn associated with nAChRs leading to a "partial" state of T cell activation resulting in T cell anergy. These studies will help in elucidating the molecular mechanism for immunomodulation by neuro- and immuno- active drugs of abuse. Additionally, the results may provide insight into the mechanism of T cell tolerance and neuroimmune interactions.