AJP - Regulatory, Integrative and Comparative Physiology, Vol 273, Issue 3 873-R879, Copyright © 1997 by American Physiological Society

ARTICLES

Attenuation of lipopolysaccharide fever in rats by protein kinase C inhibitors

W. Kozak, J. J. Klir, C. A. Conn and M. J. Kluger
Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108, USA.

The purpose of this study was to assess the effects of inhibitors of protein kinase C (PKC) on lipopolysaccharide (LPS)-induced fever and changes in circulating interleukin-6 (IL-6) levels in freely moving biotelemetered rats. We used PKC inhibitors with different inhibition constants (Ki): H-7 (Ki = 6 microM) and chelerythrine (Chel; Ki = 0.66 microM; a more potent PKC inhibitor). Rats were injected subcutaneously with either 3 or 15 microM/kg of these inhibitors and then 1 h later were injected intraperitoneally with LPS (50 micrograms/kg). Blood samples for IL-6 bioassay were collected 4 h after LPS injection. H-7 at lower doses did not significantly affect fever and LPS-induced elevation of circulating IL-6, whereas at a higher dose (15 microM/kg) H-7 reduced both fever and the increase of IL-6 (analysis of variance, Scheffe's test, P < 0.05). Chel (3 and 15 microM/kg) significantly reduced fever and almost completely inhibited the LPS-induced elevation of plasma IL-6. In separate experiments, we studied the effect of H-7 on antipyresis due to dexamethasone (Dex). Dex at a dose of 0.6 microM/kg given subcutaneously 1 h before LPS partially prevented fever (approximately 55% inhibition) and attenuated the increase of IL-6 (P < 0.05). Simultaneous pretreatment of the rats with Dex and H-7 (3 microM/kg; a dose that did not affect fever and IL-6 elevation) led to a potentiation of the antipyretic effect of Dex, resulting in no fever. H-7 did not potentiate, however, the inhibitory effect of Dex on LPS-induced elevation of circulating IL-6. We conclude that PKC is involved in the regulation of LPS fever and constitutes a rate-limiting factor in modulation of the fever by glucocorticoids.

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