Myeloid-Derived Nf-Kappa B Negative Regulation Of Pu.1 And C/Ebp-Beta-Driven Pro-Inflammatory Cytokine Production Restrains Lps-Induced Shock

Sepsis is a life-threatening event predominantly caused by Gram-negative bacteria. Bacterial infection causes a pronounced macrophage (M Phi) and dendritic cell activation that leads to excessive pro-inflammatory cytokine IL-1 beta, IL-6 and TNF-alpha production (cytokine storm), resulting in endotoxic shock. Previous experimental studies have revealed that inhibiting NF-kappa B signaling ameliorates disease symptoms; however, the contribution of myeloid p65 in endotoxic shock remains elusive. In this study, we demonstrate increased mortality in mice lacking p65 in the myeloid lineage (p65(Delta mye)) compared with wild type mice upon ultra-pure LPS challenge. We show that increased susceptibility to LPS-induced shock was associated with elevated serum level of IL-1 beta and IL-6. Mechanistic analyses revealed that LPS-induced proinflammatory cytokine production was ameliorated in p65-deficient bone marrow-derived M Phi s; however, p65-deficient ` activated' peritoneal M Phi s exhibited elevated IL-1 beta and IL-6. We show that the elevated pro-inflammatory cytokine secretion was due, in part, to increased accumulation of IL-1 beta mRNA and protein in activated inflammatory M Phi s. The increased IL-1 beta was linked with heightened binding of PU.1 and CCAAT/enhancer binding protein-beta to Il1b and Il6 promoters in activated inflammatory M Phi s. Our data provide insight into a role for NF-kB in the negative regulation of pro-inflammatory cytokines in myeloid cells.