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The protein kinase C activator PMA modulates LPS lethality in normal mice and protects against LPS lethality in D-galactosamine-sensitized mice

Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas, USA

W.M. Johnson

Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas, USA

S.E. Bucklin

Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas, USA

D.C. Johnson

Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, Kansas, USA, Department of Physiology, University of Kansas Medical Center, Kansas City, Kansas, USA

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 TNF response to LPS. In mice sensitized with D-galactosamine the same PMA pretreatment offered protection against challenge from either LPS or TNF. This protection, coupled with the ability of PMA to reduce serum TNF 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 (4-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.

Journal of Endotoxin Research, Vol. 3, No. 1, 29-37 (1996)
DOI: 10.1177/096805199600300104


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