Suppression of murine endotoxic shock by sPLA2 inhibitor,indoxam, through group IIA sPLA2-independent mechanisms

Endotoxic shock is a systemic inflammatory process, involving a variety of proinflammatory mediators. Two types of secretory phospholipase A₂ (sPLA₂) have been implicated in this process. Group IB sPLA₂ (PLA₂-IB) binds to the PLA₂ receptor (PLA₂R), and PLA₂R-deficient mice exhibit resistance to endotoxin-induced lethality with reduced plasma levels of proinflammatory cytokines, such as TNF-α. Group IIA sPLA₂ (PLA₂-IIA) is found in many tissues and cell types, and local and systemic levels are elevated under numerous inflammatory conditions including sepsis. In this study, we investigated the effect of a specific sPLA₂ inhibitor, indoxam, on murine endotoxic shock. Indoxam suppressed the elevation of plasma TNF-α with a similar potency in PLA₂-IIA-expressing and PLA₂-IIA-deficient mice after LPS challenge. In PLA₂-IIA-deficient mice, indoxam also suppressed the elevation of plasma IL-1β, IL-6 and NO, and prolonged survival after LPS challenge. Indoxam was found to block the PLA₂-IB binding to murine PLA₂R with a high potency (K_i=30 nM). The inhibitory effects of indoxam on the LPS-induced elevation of plasma TNF-α levels could not be observed in mice deficient in PLA₂R. These findings suggest that indoxam blocks the production of proinflammatory cytokines during endotoxemia through PLA₂-IIA-independent mechanisms, possibly via blockade of the PLA₂R function.