Institute for Translational Medicine, Medical School, University of Pecs, Pecs, Hungary.
Momentum Gastroenterology Multidisciplinary Research Group, Hungarian Academy of Sciences - University of Szeged, Szeged, Hungary.
Front Immunol. 2018 Feb 5;9:166. doi: 10.3389/fimmu.2018.00166. eCollection 2018.
Neurokinin (NK) signaling is involved in various inflammatory processes. A common manifestation of systemic inflammation is fever, which is usually induced in animal models with the administration of bacterial lipopolysaccharide (LPS). A role for the NK1 receptor was shown in LPS-induced fever, but the underlying mechanisms of how the NK1 receptor contributes to febrile response, especially in the early phase, have remained unknown. We administered LPS (120 µg/kg, intraperitoneally) to mice with the gene, i.e., the gene encoding the NK1 receptor, either present ( ) or absent ( ) and measured their thermoregulatory responses, serum cytokine levels, tissue cyclooxygenase-2 (COX-2) expression, and prostaglandin (PG) E concentration. We found that the LPS-induced febrile response was attenuated in compared to their littermates starting from 40 min postinfusion. The febrigenic effect of intracerebroventricularly administered PGE was not suppressed in the mice. Serum concentration of pyrogenic cytokines did not differ between and at 40 min post-LPS infusion. Administration of LPS resulted in amplification of COX-2 mRNA expression in the lungs, liver, and brain of the mice, which was statistically indistinguishable between the genotypes. In contrast, the LPS-induced augmentation of COX-2 protein expression was attenuated in the lungs and tended to be suppressed in the liver of mice compared with mice. The mice responded to LPS with a significant surge of PGE production in the lungs, whereas mice did not. In conclusion, the NK1 receptor is necessary for normal fever genesis. Our results suggest that the NK1 receptor contributes to the early phase of LPS-induced fever by enhancing COX-2 protein expression in the periphery. These findings advance the understanding of the crosstalk between NK signaling and the "cytokine-COX-2-prostaglandin E" axis in systemic inflammation, thereby open up the possibilities for new therapeutic approaches.
神经激肽（NK）信号参与各种炎症过程。全身炎症的一个常见表现是发热，通常通过给动物模型注射细菌脂多糖（LPS）来诱导发热。NK1 受体在 LPS 诱导的发热中起作用，但 NK1 受体如何参与发热反应，特别是在早期阶段，其潜在机制仍不清楚。我们给 基因（即编码 NK1 受体的基因）存在（ ）或不存在（ ）的小鼠注射 LPS（120µg/kg，腹腔内），并测量它们的体温调节反应、血清细胞因子水平、组织环氧化酶-2（COX-2）表达和前列腺素（PG）E 浓度。我们发现，与 同窝小鼠相比， 小鼠从 LPS 注射后 40 分钟开始，LPS 诱导的发热反应减弱。脑室注射 PGE 引起的发热作用在 小鼠中未被抑制。LPS 注射后 40 分钟， 和 小鼠的发热细胞因子血清浓度没有差异。LPS 给药导致小鼠肺、肝和脑中 COX-2 mRNA 表达增强，两种基因型之间无统计学差异。相比之下，与 小鼠相比，LPS 诱导的 COX-2 蛋白表达增强在肺中减弱，在肝中趋于被抑制。与 小鼠相比， 小鼠对 LPS 反应时，肺中 PGE 产生明显增加，而 小鼠则没有。总之，NK1 受体是正常发热发生所必需的。我们的结果表明，NK1 受体通过在外周组织中增强 COX-2 蛋白表达来促进 LPS 诱导的发热的早期阶段。这些发现促进了对 NK 信号与全身炎症中“细胞因子-COX-2-前列腺素 E”轴之间串扰的理解，从而为新的治疗方法开辟了可能性。
