THE PROTEIN-KINASE-C ACTIVATOR PMA MODULATES LPS LETHALITY IN NORMAL MICE AND PROTECTS AGAINST LPS LETHALITY IN D-GALACTOSAMINE-SENSITIZED MICE

Pretreatment for 5 h with 10 mu g phorbol-12-myristate-13-acetate (PMA ), a well established activator of protein kinase C (PKC) in many kind s 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 TNF alpha response to LPS. In mice sensitized with D-galactosamine th e same PMA pretreatment offered protection against challenge from eith er LPS or TNF alpha. This protection, coupled with the ability of PMA to reduce serum TNF alpha while increasing serum corticosterone in res ponse to LPS, adds in vivo support for a possible role for PKC activat ion in early endotoxin tolerance. A phorbol ester (4 alpha-phorbol) th at 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 up on a decrease in body temperature per se, but was dependent upon admin istration of PMA at the same time or prior to LPS.