Delineation of the Role of Toll-like Receptor Signaling during Peritonitis by a Gradually Growing Pathogenic Escherichia coli

作者：van 't Veer Cornelis^*; van den Pangaart Petra S; Kruijswijk Danielle; Florquin Sandrine; de Vos Alex F; van der Poll Tom

来源：Journal of Biological Chemistry, 2011, 286(42): 36603-36618.

DOI：10.1074/jbc.M110.189126

In a mouse model of Escherichia coli sepsis characterized by a primary peritoneal infection with 10(4) E. coli and a gradually growing bacterial load, we here show that the early cytokine response and antibacterial defense are dominated by TLR4 via a cooperative action of MyD88 and Trif. Although MyD88(-/-) mice succumbed earlier than WT mice in this E. coli peritonitis model, Trif(-/-) mice displayed a small but significant survival advantage. Despite a large early deficit in antimicrobial defense, TLR4(-/-) mice showed an unaltered survival with normal neutrophil attraction to the peritoneal cavity and normal or even elevated late cytokine release. TLR2 compensated for the lack of TLR4 because TLR2(-/-)/TLR4(-/-) mice did show decreased neutrophil attraction and increased mortality compared with WT mice. Nearly normal early peritoneal TNF alpha production and lack of early counterregulating systemic levels of the chemoattractant KC were associated with normal peritoneal neutrophil attraction in TLR4(-/-) mice. Late stage increased TNF, IL-1 beta, IFN-beta, and typical IFN-gamma production in TLR4(-/-) mice prompted us to evaluate expression of the negative feedback regulator SOCS-1. Lack of early hepatic SOCS-1 expression in TLR4(-/-) mice explained the late innate production of IFN-gamma by the liver in TLR4(-/-) mice in this low dose E. coli peritonitis model. In contrast, early TLR4-induced IFN-gamma production is described as a hallmark in high dose E. coli peritonitis models. The present study displays how the kinetics of pro-and anti-inflammatory mechanisms are regulated by TLRs during peritonitis by a gradually growing E. coli load and how these kinetics may affect outcome.

• 出版日期2011-10-21