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.
|Zhou, D; Brown, S A; Yu, T et al. (1999) A high dose of ionizing radiation induces tissue-specific activation of nuclear factor-kappaB in vivo. Radiat Res 151:703-9|