Bikunin suppresses lipopolysaccharide-induced lethality through down-regulation of tumor necrosis factor-α and interleukin-1β in macrophages

Abstract

Background. Lipopolysaccharide (LPS) is the primary mediator of gram-negative sepsis; it induces the production of macrophage-derived cytokines. It has been shown that bikunin, a Kunitz-type protease inhibitor, inhibits LPS-induced cytokine expression. Methods. To explore the role of bikunin, bikunin knockout (Bik-/-) mice were used for in vitro cytokine experiments and in vivo animal models. Results. We show that a higher level of LPS-mediated death was induced in Bik-/-, compared with wild-type (wt), mice; the administration of bikunin caused a significant reduction in LPS-induced lethality; LPS significantly increased tumor necrosis factor (TNF)-α and interleukin-1β levels in Bik-/-, relative to wt, mice after LPS challenge; concomitant administration of bikunin inhibited the LPS-induced plasma levels of these cytokines; bikunin suppressed the LPS-induced up-regulation of cytokine expression through the suppression of the phosphorylation of ERK1/2, JNK, and p38 in macrophages; and LPS-induced up-regulation of TNF-α expression was not enhanced in Bik-/- macrophages without endogenous bikunin. Conclusions. These data allow us to speculate that the increased sensitivity of Bik-/- mice to LPS-induced death in vivo is due to a lack of circulating bikunin in plasma. Bikunin may play a role as a potent anti-inflammatory agent. © 2005 by the Infectious Diseases Society of America. All rights reserved.