STRESSOR INDUCED MODULATION OF INDUCIBLE NO PRODUCTION

描述(改编自申请者的摘要)：老鼠暴露于 条件性厌恶刺激(CS)或一次16足电击(FS) 抑制脾淋巴细胞有丝分裂反应(SLMR)。这个 调查人员的初步研究以及其他人的研究表明 应激诱导的SLMR抑制是由巨噬细胞来源的 一氧化氮(NO)，而CS增加脾巨噬细胞NO的产生 抑制SLMR，FS可能提高脾淋巴细胞对SLMR的敏感性 巨噬细胞来源的NO的抑制作用。封锁外围设备 β-肾上腺素能受体(B-AR)与脑垂体精氨酸耗竭 加压素(AVP)，或称脑下垂体切除术，可以改善应激源诱导的 抑制SLMR，抑制脾巨噬细胞NO的产生。这 提示儿茶酚胺(CA)和AVP参与调节 巨噬细胞NO的产生与应激诱导的SLMR在此应用程序中， 研究人员将研究脾的交感神经调节机制 巨噬细胞NO的产生通过检查：(A) CS和FS对脾巨噬细胞诱导型一氧化氮合酶的不同调节作用 (B)尖锐湿疣患者外周血中NO、IL-1、TNF的表达。 NO产生的增加是由一种脱敏和 脾组织中下调的B2-AR或不典型的B-AR(如B3-AR) 巨噬细胞，因为只有非常高浓度的CA才能增强脾 巨噬细胞NO的产生；(C)CA是否参与脑啡肽的共同传递， 神经肽Y(NPY)和腺苷能够调节肾上腺素能 调节脾巨噬细胞一氧化氮的产生；及(D) FS不能增加NO的产生是由于FS刺激的释放 NPY和腺苷，这可能构成一种负反馈机制 限制CA对脾巨噬细胞NO生成的影响。此外， 研究人员将确定G蛋白-腺苷的作用 Cyclase-cAMP-PKA信号转导通路与核转录 核因子-kB和AP-1在脾交感神经调节中的作用 巨噬细胞诱导型一氧化氮合酶的表达和一氧化氮的产生。最后，他们将学习 AVP调节脾巨噬细胞产生NO的机制 并确定AVP是否参与应激源诱导的SLMR。这些 研究旨在促进我们对神经激素调节的理解。 脾巨噬细胞NO的产生，不仅对揭示 应激诱导免疫抑制的机制及研究方向 巨噬细胞防御功能。

DESCRIPTION (Adapted from applicant's abstract): Exposure of rats to a conditioned aversive stimulus (CS) or a session of 16 footshocks (FS) suppresses splenic lymphocyte mitogenic responses (SLMR). The investigators' preliminary studies as well as that of others have shown that stressor-induced suppression of SLMR is mediated by macrophage-derived nitric oxide (NO), while CS increases splenic macrophage NO production to suppress SLMR, and FS may increase the sensitivity of spleen lymphocytes to the inhibitory effects of macrophage-derived NO. Blockade of peripheral beta-adrenergic receptors (B-AR), depletion of pituitary arginine vasopressin (AVP), or hypophysectomy, can ameliorate stressor-induced suppression of SLMR and inhibit splenic macrophage NO production. This suggests that catecholamines (CA) and AVP are involved in modulating macrophage NO production and stress-induced SLMR. In this application, the investigators will study the mechanisms of sympathetic regulation of splenic macrophage NO production in response to CS or FS by examining: (a) whether CS and FS differentially regulate splenic macrophage inducible NO synthase (iNOS) and cytokines IL-1 and TNF mRNA expression; (b) whether CA augmentation of NO production is mediated by a desensitized and down-regulated B2-AR or an atypical B-AR (such as B3-AR) on splenic macrophages, since only very high concentrations of CA can enhance splenic macrophage NO production; (c) whether CA co-transmitters of enkephalin, neuropeptide Y (NPY), and adenosine are capable of modulating adrenergic regulation of splenic macrophage NO production; and (d) whether the incapability of FS to enhance NO production is due to FS-stimulated release of NPY and adenosine, which may constitute a negative feedback mechanism to limit CA affecting splenic macrophage NO production. In addition, the investigators will determine the roles of the G proteins-adenyl cyclase-cAMP-PKa signal traduction pathway and nuclear transcriptional factors of NF-kB and AP-1 in mediating sympathetic regulation of splenic macrophage iNOS mRNA expression and NO production. Finally, they will study the mechanisms of AVP regulation of NO production by splenic macrophages, and determine whether AVP is involved in stressor-induced SLMR. These studies aim to advance our understanding of the neurohormonal regulation of splenic macrophage NO production, which is not only important for revealing the mechanisms of stressor-induced immunosuppression but also for studying macrophage defensive function.