STRESSOR INDUCED MODULATION OF INDUCIBLE NO PRODUCTION

描述（改编自申请人摘要）：大鼠暴露于 条件厌恶刺激（CS）或16次足底电击（FS） 抑制脾淋巴细胞有丝分裂反应（SLMR）。 的 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抑制由巨噬细胞源性 一氧化氮（NO），而CS增加脾巨噬细胞NO的产生， 抑制SLMR，FS可增加脾淋巴细胞对 巨噬细胞源性外周血NO阻断的抑制作用 β-肾上腺素能受体（B-AR），垂体精氨酸耗竭 加压素（AVP）或垂体切除术可以改善应激诱导的 抑制SLMR和抑制脾巨噬细胞NO产生。 这 表明，儿茶酚胺（CA）和AVP参与调节 巨噬细胞NO产生和应激诱导的SLMR。 在本申请中， 研究人员将研究脾交感神经调节的机制， 巨噬细胞NO的产生响应CS或FS通过检查：（a）是否 CS和FS对脾巨噬细胞诱导型NO合酶的调节作用 （B）CA是否与细胞因子IL-1和TNF mRNA的表达有关; NO产生的增加是由一种脱敏的， 脾细胞上B2-AR或非典型B-AR（如B3-AR）下调 巨噬细胞，因为只有非常高浓度的CA可以增强脾细胞的免疫功能。 巨噬细胞NO产生;（c）是否CA脑啡肽的共递质， 神经肽Y（NPY）和腺苷能够调节肾上腺素能 调节脾巨噬细胞NO的产生;和（d）是否 FS不能促进NO的产生是由于FS刺激的释放 NPY和腺苷，这可能构成负反馈机制， 限制CA影响脾巨噬细胞NO产生。 此外该 研究人员将确定G蛋白的作用-腺苷酸 环化酶-cAMP-PKa信号转导通路与核转录 NF-kB和AP-1在脾交感神经调节中的作用 巨噬细胞iNOSmRNA表达和NO产生。 最后，他们将研究 AVP调节脾巨噬细胞产生NO的机制， 并确定AVP是否参与应激诱导的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，这不仅是重要的揭示 应激诱导免疫抑制的机制， 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.