The Neurokinin-1 receptor contributes to the early phase of lipopolysaccharide-induced fever via stimulation of peripheral cyclooxygenase-2 protein expression in mice

Eszter Pakai, Valeria Tekus, Csaba Zsiboras, Zoltan Rumbus, Emoke Olah, Patrik Keringer, Nora Khidhir, Robert Matics, Laszlo Deres, Katalin Ordog, Nikolett Szentes, Krisztina Pohoczky, Agnes Kemeny, Peter Hegyi, Erika Pinter, Andras Garami

Research output: Article

6 Citations (Scopus)

Abstract

eurokinin (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 Tacr1 gene, i.e., the gene encoding the NK1 receptor, either present (Tacr1+/+) or absent (Tacr1-/-) and measured their thermoregulatory responses, serum cytokine levels, tissue cyclooxygenase-2 (COX-2) expression, and prostaglandin (PG) E2 concentration. We found that the LPS-induced febrile response was attenuated in Tacr1-/- compared to their Tacr1+/+ littermates starting from 40 min postinfusion. The febrigenic effect of intracerebroventricularly administered PGE2 was not suppressed in the Tacr1-/- mice. Serum concentration of pyrogenic cytokines did not differ between Tacr1-/- and Tacr1+/+ 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 Tacr1-/- mice compared with Tacr1+/+ mice. The Tacr1+/+ mice responded to LPS with a significant surge of PGE2 production in the lungs, whereas Tacr1-/- 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 E2" axis in systemic inflammation, thereby open up the possibilities for new therapeutic approaches.

Original languageEnglish
Article number166
JournalFrontiers in immunology
Volume9
Issue numberFEB
DOIs
Publication statusPublished - febr. 5 2018

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint Dive into the research topics of 'The Neurokinin-1 receptor contributes to the early phase of lipopolysaccharide-induced fever via stimulation of peripheral cyclooxygenase-2 protein expression in mice'. Together they form a unique fingerprint.

  • Cite this

    Pakai, E., Tekus, V., Zsiboras, C., Rumbus, Z., Olah, E., Keringer, P., Khidhir, N., Matics, R., Deres, L., Ordog, K., Szentes, N., Pohoczky, K., Kemeny, A., Hegyi, P., Pinter, E., & Garami, A. (2018). The Neurokinin-1 receptor contributes to the early phase of lipopolysaccharide-induced fever via stimulation of peripheral cyclooxygenase-2 protein expression in mice. Frontiers in immunology, 9(FEB), [166]. https://doi.org/10.3389/fimmu.2018.00166