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Role of CINC-1 and CXCR2 receptors on LPS-induced fever in rats

  • Integrative Physiology
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Abstract

The classic model of fever induction is based on the administration of lipopolysaccharide (LPS) from Gram-negative bacteria in experimental animals. LPS-induced fever results in the synthesis/release of many mediators that assemble an LPS-fever cascade. We have previously demonstrated that cytokine-induced neutrophil chemoattractant (CINC)-1, a Glu-Leu-Arg (ELR) + chemokine, centrally administered to rats, induces fever and increases prostaglandin E2 in the cerebrospinal fluid. We now attempt to investigate the involvement of CINC-1 and its functional receptor CXCR2 on the fever induced by exogenous and endogenous pyrogens in rats. We also investigated the effect of reparixin, an allosteric inhibitor of CXCR1/CXCR2 receptors, on fever induced by either systemic administration of LPS or intracerebroventricular injection of CINC-1, as well as TNF-α, IL-1β, IL-6, or ET-1, known mediators of febrile response. Our results show increased CINC-1 mRNA expression in the liver, hypothalamus, CSF, and plasma following LPS injection. Moreover, reparixin administered right before CINC-1 or LPS abolished the fever induced by CINC-1 and significantly reduced the response induced by LPS. In spite of these results, reparixin does not modify the fever induced by IL-1β, TNF-α, and IL-6, but significantly reduces ET-1-induced fever. Therefore, it is plausible to suggest that CINC-1 might contribute to LPS-induced fever in rats by activating CXCR2 receptor on the CNS. Moreover, it can be hypothesized that CINC-1 is placed upstream TNF-α, IL-1β, and IL-6 among the prostaglandin-dependent fever-mediator cascade and amidst the prostaglandin-independent synthesis pathway of fever.

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Acknowledgements

We are most grateful to Aparecida Rosa da Silva, Miriam C. C. Melo, and Juliana Vercesi for their expert technical assistance.

Funding

This study was funded by FAPESP (Proc. 050/2008), FAPESB (RED014/2013), and CNPq (Proc. 302575/2015-4).

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Author notes

  1. Lívia Harumi Yamashiro

    Present address: Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA

Authors and Affiliations

  1. Laboratory of Pharmacology, Department of Physic and Chemistry, Faculty of Pharmaceutical Science, University of São Paulo, Ribeirão Preto, SP, Brazil

    Lívia Harumi Yamashiro & Glória Emília Petto de Souza

  2. Faculdade de Farmácia, Universidade Federal da Bahia, Rua Barão do Jeremoabo, no. 147, Ondina, Salvador, Bahia, 40170-115, Brazil

    Denis de Melo Soares

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  1. Lívia Harumi Yamashiro
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All experiments were previously approved by the Ethical Commission of Ethics in Animal Research of the College of Medicine of Ribeirão Preto University of São Paulo (protocol no. 050/2008) and were performed in accordance with the Guide for the Care and Use of Laboratory Animals of the Institute for Laboratory Animal Research (1996).

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Yamashiro, L.H., de Souza, G.E.P. & de Melo Soares, D. Role of CINC-1 and CXCR2 receptors on LPS-induced fever in rats. Pflugers Arch - Eur J Physiol 471, 301–311 (2019). https://doi.org/10.1007/s00424-018-2222-0

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