Singh S P, Kalra R, Puttfarcken P, Kozak A, Tesfaigzi J, Sopori M L
Pathophysiology Division, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87185, USA.
Toxicol Appl Pharmacol. 2000 Apr 1;164(1):65-72. doi: 10.1006/taap.2000.8897.
We have previously shown that T cells from rats exposed chronically to cigarette smoke or nicotine (NT) exhibit T cell anergy and decreased proliferation to T cell mitogens. Effects of chronic NT on T cell function persist for at least 2 weeks after the termination of NT treatment. Moreover, these effects of NT are causally related to the decreased Ca(2+) response to T cell receptor (TCR) ligation and constitutive activation of protein tyrosine kinase (PTK) and phospholipase C (PLC)-gamma1 activities. Acute NT treatment also suppresses the Con A-induced T cell proliferation; however, it is not known whether the mechanism(s) by which acute and chronic NT treatments inhibit T cell proliferation are identical. To evaluate this question, LEW rats were acutely treated with NT (1 mg/kg body wt) for 1, 2, or 24 h by an ip injection or implanted with constant-release miniosmotic pumps containing saline or NT (1 mg/kg body wt/day) for a 3-week chronic exposure. Inhibition of Con A-induced proliferation of peripheral blood cells (PBC) by both acute and chronic treatments was reversed by the inhibitor of nicotinic acetylcholine receptors, mecamylamine (MEC), indicating that these receptors are required for T cell proliferation. However, the effect of acute NT on the Con A response was short lived (i.e., observed at 1 and 2 h but not at 24 h after NT administration) and was seen in PBC but not in spleen cells. Unlike the chronic treatment, acute NT administration neither suppressed significantly the TCR-mediated Ca(2+) response nor did it cause the constitutive activation of PTK and PLC-gamma1 activities in blood lymphocytes. Acute, but not chronic, NT administration increased the plasma corticosterone concentration, and this increase was also inhibited by MEC. Moreover, adrenalectomy abrogated the acute but not chronic NT effects on the Con A response. Thus, the acute and chronic effects of NT on T lymphocytes are mechanistically distinct phenomena. Whereas chronic administration of NT causes T cell anergy, acute effects are primarily mediated via the activation of the hypothalamus-pituitary-adrenal axis.
我们之前已经表明，长期暴露于香烟烟雾或尼古丁（NT）的大鼠的T细胞表现出T细胞无反应性，并且对T细胞有丝分裂原的增殖能力下降。在NT治疗终止后，慢性NT对T细胞功能的影响至少持续2周。此外，NT的这些作用与对T细胞受体（TCR）连接的Ca(2+)反应降低以及蛋白酪氨酸激酶（PTK）和磷脂酶C（PLC）-γ1活性的组成性激活存在因果关系。急性NT治疗也会抑制刀豆蛋白A诱导的T细胞增殖；然而，急性和慢性NT治疗抑制T细胞增殖的机制是否相同尚不清楚。为了评估这个问题，通过腹腔注射对LEW大鼠进行急性NT（1mg/kg体重）治疗1、2或24小时，或者植入含有生理盐水或NT（1mg/kg体重/天）的恒速释放微型渗透泵进行为期3周的慢性暴露。烟碱型乙酰胆碱受体抑制剂美加明（MEC）可逆转急性和慢性治疗对刀豆蛋白A诱导的外周血细胞（PBC）增殖的抑制作用，表明这些受体是T细胞增殖所必需的。然而，急性NT对刀豆蛋白A反应的影响是短暂的（即在NT给药后1小时和2小时观察到，但在24小时未观察到），并且在PBC中可见，但在脾细胞中未见。与慢性治疗不同，急性NT给药既没有显著抑制TCR介导的[Ca(2+)]i反应，也没有导致血液淋巴细胞中PTK和PLC-γ1活性的组成性激活。急性而非慢性NT给药会增加血浆皮质酮浓度，并且这种增加也被MEC抑制。此外，肾上腺切除术消除了急性但非慢性NT对刀豆蛋白A反应的影响。因此，NT对T淋巴细胞的急性和慢性作用是机制上不同的现象。慢性给予NT会导致T细胞无反应性，而急性作用主要通过下丘脑-垂体-肾上腺轴的激活介导。
