MECHANISM OF CIGARETTE SMOKE-INDUCED IMMUNOSUPPRESSION

流行病学研究表明，长期吸入香烟烟雾与癌症、心脏病、呼吸道感染和包括艾滋病在内的其他感染的风险增加有关。艾滋病痴呆复合体，以及HIV-1从母亲传给后代。我们和其他人已经证明了SM会抑制免疫系统，并且已经假设SM的许多健康后果源于它对免疫系统的影响，并且已经假设SM的许多健康后果源于它对免疫系统的影响。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，长期暴露于尼古丁会引起与SM相似的免疫抑制，并在细胞周期的G0/G1期阻止T细胞。最近的数据表明，长期暴露于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隐球菌的复制和/或传播。此外，虽然在体外NT影响一些T细胞参数，但NT在体内的许多作用可能主要通过中枢神经系统介导。慢性SM或NT的免疫抑制与T淋巴细胞中抗原介导的信号通路受损有因果关系，导致T细胞能量不足。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）的内在活化，细胞因子（包括IL-2）的产生减少，有趣的是，肌醇-1,4,5-三磷酸（IP3）敏感的细胞内Ca2+（包括IL-2）减少，有趣的是，肌醇-1/4/5-三磷酸（IP3）敏感的细胞内Ca2+储存减少。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进入细胞核的运输。我们的初步结果表明，Fyn是一种与T细胞抗原受体（TCRs）和烟碱乙酰胆碱受体（nAChRs）相关的src样PTK，在nt治疗动物的T细胞中被组成性激活。有趣的是，感染了小鼠艾滋病病毒的小鼠体内的无能T细胞激活了Fyn。基于这些数据，我们假设一个组成活性的Fyn，通过消耗IP3敏感的Ca2+储存，影响转录因子从细胞质向细胞核的迁移。此外，NT特异性激活与nachr相关的Fyn，导致T细胞激活的“部分”状态，从而导致T细胞能量。这些研究将有助于阐明滥用神经和免疫活性药物对免疫调节的分子机制。此外，该结果可能为T细胞耐受性和神经免疫相互作用的机制提供见解。

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.