Prevention of endotoxin-induced lethality in mice by calmodulin kinase activator

Porphyromonas gingivalis strain 381 lipid A showed lower activity in inducing interleukin (IL)-1α and IL-1β production and cytokine mRNA expression than synthetic Escherichia coli lipid A (compound 506) in alveolar macrophages of C57BL/6 mice. Both the lipid As induced tumor necrosis factor α in alveolar macrophages and IL-6 in peritoneal macrophages. A calmodulin (CaM) antagonist, W-7, inhibited IL-1β production and its mRNA expression induced by P. gingivalis lipid A but not compound 506 in alveolar macrophages. A CaM kinase activator reduced the induction of IL-1β in the serum of mice when administered with compound 506, and protected the mice against the lethal toxicity. The modulation of a variety of intracellular enzymes including the CaM kinase may result in clinical control of endotoxic sepsis.