Critical role of CD14 for production of proinflammatory cytokines and cytokine inhibitors during sepsis with failure to alter morbidity or mortality

We investigated the immunopathophysiologic responses during sepsis induced by cecal ligation and puncture (CLP) in CD4-deficient (CD14 knockout [CD14K O]) mice. Our studies were designed to specifically test the role of CD14 i n the inflammatory response to sepsis and to ascertain if alterations would improve morbidity or mortality. Sepsis was induced using the CLP model wit h appropriate antibiotic treatment. The severity of sepsis increased in the CD14KO mice with increasing puncture size (18 gauge [18G], 21G, and 25G). Following CLP, body temperature (at 12 h) and gross motor activity levels o f the sham and 25G CLP groups recovered to normal, while the 21G and 18G CL P groups exhibited severe hypothermia coupled with decreased gross motor ac tivity and body weight. There were no significant differences in survival, temperature, body weight, or activity levels between CD14KO and control mic e after 21G CLP. However, CD14KO mice expressed two- to fourfold less pro-i nflammatory (interleukin-1 beta [IL-1 beta], tumor necrosis factor [TNF], a nd IL-6) and antiinflammatory (IL-10, IL-1 receptor antagonist, and TNF rec eptors I and II) cytokines in the blood after 21G CLP. Plasma levels of the chemokines macrophage inflammatory protein 2 alpha and KC were similarly r educed in CD14KO mice. A similar trend of decreased cytokine and cytokine i nhibitor levels was observed in the peritoneal cavity of CD14KO mice. Our r esults indicate that the CD14 pathway of activation plays a critical role i n the production of both pro inflammatory cytokines and cytokine inhibitors but has minimal impact on the morbidity or mortality induced by the CLP mo del of sepsis.