AJP - Endocrinology and Metabolism, Vol 263, Issue 4 E632-E636, Copyright © 1992 by American Physiological Society

ARTICLES

Inhibition of central actions of cytokines on fever and thermogenesis by lipocortin-1 involves CRF

P. J. Strijbos, A. J. Hardwick, J. K. Relton, F. Carey and N. J. Rothwell
Department of Physiological Sciences, University of Manchester, Macclesfield, United Kingdom.

In the present studies, the mechanisms underlying the inhibitory actions of lipocortin-1 on the pyrogenic and thermogenic properties of cytokines were investigated. Central (icv) injection of corticotropin-releasing factor (CRF, 4.7 micrograms) or the recombinant cytokines interleukin (IL)-1 alpha (50 ng), IL-1 beta (5 ng), IL-6 (20 ng), IL-8 (20 ng), or tumor necrosis factor-alpha (TNF-alpha, 1 microgram) in conscious rats produced significant increases in resting oxygen consumption (VO2, 13-26%) and colonic temperature (0.7-1.6 degrees C) within 2 h postinjection. Administration (icv) of a recombinant fragment (NH2-terminus, 1-188 amino acids) of human lipocortin-1 (1.2 micrograms) produced small increases in VO2 (< 5%) and body temperature (< 0.3 degrees C). Pretreatment (-5 min) with lipocortin-1 significantly attenuated the thermogenic and pyrogenic effects of centrally injected IL-1 beta (80% inhibition), IL-6 (60%), IL-8 (80%), or CRF (60%). However, pretreatment with lipocortin-1 failed to modify the actions of IL-1 alpha or TNF-alpha. We have previously demonstrated that the pyrogenic and thermogenic effects of IL-1 beta, IL-6, and IL-8 are dependent on the central actions of CRF, whereas IL-1 alpha and TNF-alpha act independently of CRF. Fever and thermogenesis induced by all of these cytokines (with the exception of IL-8) can also be prevented by administration of a cyclooxygenase inhibitor. The data presented here suggest that the potent antipyretic effects of lipocortin-1 may result from inhibition of the release or actions of CRF rather than modulation of eicosanoid synthesis.

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