Pretreatment for 5 h with 10 μg phorbol-12-myristate-13-acetate (PMA), a well established activator of protein kinase C (PKC) in many kinds of cells including macrophages, was found to either (a) delay, or (b) potentiate, lethal endotoxin shock in mice, depending upon the dose of LPS. The latter occurred despite a marked attenuation (>90%) of the TNFα response to LPS. In mice sensitized with D-galactosamine the same PMA pretreatment offered protection against challenge from either LPS or TNFα. This protection, coupled with the ability of PMA to reduce serum TNFα while increasing serum corticosterone in response to LPS, adds in vivo support for a possible role for PKC activation in early endotoxin tolerance. A phorbol ester (4α-phorbol) that is not a PKC activator was found ineffective. PMA produced a prompt and profound decrease in body temperature which reached a nadir at 3 h. However, the protective effect produced by PMA was not dependent upon a decrease in body temperature per se, but was dependent upon administration of PMA at the same time or prior to LPS.
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