. Hyperthermia-enhanced splenic cytokine gene expression is mediated by the sympathetic nervous system. Physiol Genomics 19: 175-183, 2004. First published August 3, 2004 doi:10.1152/physiolgenomics.00109.2004.-Whole body hyperthermia (WBH) has been used in experimental settings as an adjunct to radiochemotherapy for the treatment of various malignant diseases. The therapeutic effect of WBH has been hypothesized to involve activation of the immune system, although the effect of hyperthermia-induced activation of sympathetic nerve discharge (SND) on splenic immune function is not known. We tested the hypothesis that heating-induced splenic sympathoexcitation would alter splenic cytokine gene expression as determined using gene array and real-time RT-PCR analyses. Experiments were performed in splenic-intact and splenic-denervated anesthetized Sprague-Dawley rats (n ϭ 32). Splenic SND was increased during heating (internal temperature increased from 38°to 41°C) in splenic-intact rats but remained unchanged in nonheated splenic-intact rats. Splenic interleukin-1 (IL-1), interleukin-6 (IL-6), and growth-regulated oncogene 1 (GRO 1) mRNA expression was higher in heated than in nonheated splenic-intact rats. Splenic IL-1, IL-6, and GRO 1 mRNA expression was reduced in heated splenic-denervated compared with heated splenic-intact rats, but did not differ between heated splenicdenervated and nonheated splenic-intact rats. These results support the hypothesis that hyperthermia-induced activation of splenic SND enhances splenic cytokine gene expression. whole body hyperthermia; sympathetic nerve discharge; sympathoexcitation; splenic denervation WHOLE BODY HYPERTHERMIA (WBH) profoundly influences sympathetic nerve regulation. Increased internal body temperature produced by whole body heating increases muscle sympathetic nerve discharge (SND) in conscious humans (10-12, 50), splanchnic SND in conscious rats (36), and renal, splanchnic, and splenic sympathetic nerve activity in anesthetized rats (22,(29)(30)(31)33) and decreases SND directed to the caudal ventral artery in the rat (27). Moreover, moderate body warming decreases skin sympathetic nerve activity in human subjects (13). Hyperthermia-induced increases in visceral SND are attenuated during acute heating in cervical transected rats (33), supporting an important role for supraspinal neural circuits in mediating visceral sympathetic nerve responses to increased internal body temperature.WBH has been used in experimental settings as an adjunct to radiochemotherapy for the treatment of various malignant diseases (20, 58). The therapeutic effect of WBH in these conditions has been hypothesized to involve activation of the immune system (5, 51, 52). Robins et al. (52) reported elevated plasma levels of granulocyte-colony stimulating factor, interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8, interleukin-10, and tumor necrosis factor-␣ (TNF-␣) when WBH was used in conjunction with chemotherapy in human patients. Atanackovic et al. (5) reported that human pat...