ATTENUATION OF LIPOPOLYSACCHARIDE FEVER IN RATS BY PROTEIN-KINASE-C INHIBITORS

The purpose of this study was to assess the effects of inhibitors of p rotein kinase C (PKC) on lipopolysaccharide (LPS)-induced fever and ch anges in circulating interleukin-6 (IL-6) levels in freely moving biot elemetered rats. We used PKC inhibitors with different inhibition cons tants (K-i): H-7 (K-i = 6 mu M) and chelerythrine (Chel; K-i = 0.66 mu M; a more potent PKC inhibitor). Rats were injected subcutaneously wi th either 3 or 15 mu M/kg of these inhibitors and then 1 h later were injected intraperitoneally with LPS (50 mu g/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 circu lating IL-6, whereas at a higher dose (15 mu M/kg) H-7 reduced both fe ver and the increase of IL-6 (analysis of variance, Scheffe's test, P < 0.05). Chel (3 and 15 mu M/kg) significantly reduced fever and almos t completely inhibited the LPS-induced elevation of plasma IL-6. In se parate experiments, we studied the effect of H-7 on antipyresis due to dexamethasone (Dex). Dex at a dose of 0.6 mu M/kg given subcutaneousl y 1 h before LPS partially prevented fever (similar to 55% inhibition) and attenuated the increase of IL-6 (P < 0.05). Simultaneous pretreat ment of the rats with Dex and H-7 (3 mu M/kg; a dose that did not affe ct 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 g lucocorticoids.