MECHANISM OF CIGARETTE SMOKE-INDUCED IMMUNOSUPPRESSION

流行病学研究表明，长期吸入香烟烟雾（SM）与癌症，心脏病，呼吸道感染和其他感染（包括艾滋病）的风险增加有关。艾滋病痴呆综合症，以及HIV-1从母亲传播给后代。我们和其他人已经表明SM抑制免疫系统，并且已经假设SM的许多健康后果是由于其对免疫系统的影响，并且已经假设SM的许多健康后果是由于其对免疫系统的影响。尼古丁（NT）是SM中最重要的免疫活性物质，我们的实验室是第一个证明长期暴露于NT会引起与SM相似的免疫抑制，并将T细胞阻滞在细胞周期的G 0/G1期。最近的数据表明，长期暴露于NT，虽然抗炎，增加复制和/或传播的流感病毒和酵母样真菌，新型隐球菌。此外，虽然在体外NT影响一些T细胞参数，NT的许多体内效应可能主要通过CNS介导。慢性SM或NT引起的免疫抑制与T淋巴细胞中抗原介导的信号传导受损有关，导致T细胞无反应性。我们的初步结果表明，这些无能的T细胞表现出内在激活的蛋白酪氨酸激酶（PTKs），减少细胞因子的产生，包括IL-2，和，有趣的是，耗尽肌醇-1，4，5-三磷酸（IP 3）敏感的细胞内钙离子，包括IL-2，和，有趣的是，耗尽肌醇-1/4/5-三磷酸（IP 3）敏感的细胞内钙储存。这些储存对于T细胞功能至关重要，包括抗原/有丝分裂原诱导的增殖和转录因子转运到细胞核中。我们的初步结果表明，Fyn，一个Src样PTK发现与T细胞抗原受体（TCR）和烟碱乙酰胆碱受体（nAChRs），组成性激活的T细胞从NT治疗动物。有趣的是，来自感染小鼠艾滋病病毒的小鼠的无反应性T细胞激活了Fyn。基于这些数据，我们假设，一个组成型活性Fyn，通过消耗IP 3敏感的Ca 2+商店，影响移民的转录因子从细胞质到细胞核。此外，NT特异性激活与nAChR相关的Fyn，导致T细胞活化的“部分”状态，导致T细胞无反应性。这些研究将有助于阐明滥用神经和免疫活性药物的免疫调节的分子机制。此外，这些结果可能为T细胞耐受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.