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Critical role for peripherally-derived interleukin-10 in mediating the thermoregulatory manifestations of fever and hypothermia in severe forms of lipopolysaccharide-induced inflammation

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Abstract

Although peripherally released interleukin (IL)-10 has a critical regulatory role in limiting fever in mild-to-moderate forms of inflammation, its role in regulating the more complex thermoregulatory manifestations of hypothermia and fever noted during severe inflammation is less clear. Using cytokine antagonism, we therefore investigated the involvement of peripherally released IL-10 in mediating hypothermia, fever and inflammation induced by intraperitoneal (IP) administration of a large dose of lipopolysaccharide (LPS). Male Wistar rats (200–250 g) were anaesthetized and implanted intra-abdominally with temperature-sensitive radiotelemeters. Rats were randomly assigned to receive IL-10 antiserum (IL-10AS) or normal sheep serum IP, 4 h before receiving an IP injection of LPS (10 mg/kg) or phosphate-buffered saline (PBS). Inflammatory responses were measured in plasma and tissue samples (spleen, liver and brain) at 90 min and 6 h after the IP injection of LPS or PBS. Administration of LPS induced an initial period of hypothermia (~90 min) after which fever developed. Pre-treating rats with IL-10AS abolished the LPS-induced increase in plasma IL-10 levels, attenuated the hypothermia and increased the amplitude of the fever. Moreover, IL-10AS pre-treatment augmented the LPS-induced increase in plasma levels of tumor necrosis factor-alpha (90 min and 6 h), IL-1β (90 min), prostaglandin E2 (90 min) and IL-6 (6 h), in the periphery, but not the hypothalamus, over the duration of hypothermia and fever. Via its action on the synthesis of inflammatory mediators in the spleen and liver, endogenous IL-10 plays a crucial regulatory role in mediating hypothermia and fever during severe aspectic (LPS-induced) systemic inflammation.

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Acknowledgments

We are grateful to Jolanta Murgott, Doreen Marks, Daniela Ott and Margaret Badenhorst for their expert technical assistance and to the NIBSC for providing the IL-10 antiserum. Funding for this study was provided by the Alexander von Humboldt Foundation of Germany, The Carnegie Corporation of New York and the National Research Foundation of South Africa.

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The experiments comply with the current laws of Germany in which they were performed.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Brain Function Research Group, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193, Johannesburg, South Africa

    Lois M. Harden & Helen P. Laburn

  2. Institut für Veterinär-Physiologie, Justus-Liebig-Universität Giessen, Frankfurter Strasse 100, 35392, Giessen, Germany

    Lois M. Harden, Christoph Rummel, Jelena Damm, Florian Wiegand, Rüdiger Gerstberger & Joachim Roth

  3. Biotherapeutics Group, National Institute for Biological Standards and Control, South Mimms, Potters Bar, Herts, EN6 3QG, UK

    Stephen Poole

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  1. Lois M. Harden
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Correspondence to Lois M. Harden.

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Harden, L.M., Rummel, C., Laburn, H.P. et al. Critical role for peripherally-derived interleukin-10 in mediating the thermoregulatory manifestations of fever and hypothermia in severe forms of lipopolysaccharide-induced inflammation. Pflugers Arch - Eur J Physiol 466, 1451–1466 (2014). https://doi.org/10.1007/s00424-013-1371-4

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