Cytokines and Escherichia coli Sepsis

Abstract

This review reviews the critical role played by cytokines in the pathogenesis of Escherichia coli sepsis. It focuses on prototypic pro-inflammatory and anti-inflammatory cytokines and their influence on mortality in experimental animal models of E. coli endotoxemia and of live E. coli sepsis. The review reviews the results of clinical trials on anticytokine therapy in patients with severe sepsis or septic shock. The recognition of the critical role played by tumor necrosis factor (TNF), a secreted 17kDa cytokine, in endotoxic and gram-negative shock has been a major step forward in our understanding of the pathogenesis of sepsis. The review describes the role of TNF, IL1, and IL6 in animal models of E. coli endotoxemia and sepsis. Given the pivotal role played by TNF in experimental sepsis and the fact that elevated concentrations of TNF were detected in the circulation of patients with sepsis, anti-TNF treatment strategies were investigated as adjunctive therapy for severe sepsis and septic shock. Several studies demonstrated that high levels of interleukin-6 (IL-6) are associated with an increased risk for fatal outcome. Gamma interferon (IFN-γ), IL-12, and IL-18 are functionally related cytokines. A recent study has indicated that transgenic mice overexpressing IL-15 are resistant to an otherwise lethal intraperitoneal E. coli challenge. IL4, IL10, and IL13are prototypic anti-inflammatory cytokines. Their classification as anti-inflammatory cytokines is based on the observation that these molecules inhibit the production of proinflammatory cytokines (primarily TNF and IL1) and toxic oxygen and reactive nitrogen species by myeloid cells.