REGULATION OF AN ESSENTIAL INNATE IMMUNE-RESPONSE BY THE P50 SUBUNIT OF NF-KAPPA-B

Recognition of bacterial endotoxin (LPS) elicits multiple host respons es, including activation of cells of the innate immune system. LPS exp osure occurs repeatedly during septicemia, making strict regulation of gene expression necessary. Such regulation might prevent, for example , the continuous production of proinflammatory cytokines such as tumor necrosis factor (TNF), which could lead to severe vascular collapse. Tolerance to LPS is characterized by a diminished production of TNF du ring prolonged exposure to LPS, and is therefore likely to represent a n essential control mechanism during sepsis. In the present study, whi ch uses mice with genetic deletions of the proteins of NF-kappa B comp lex, we provide data demonstrating that increased expression of the p5 0 subunit of NF-kappa B directly results in the downregulation of LPS- induced TNF production. This contention is supported by the following observations: (1) tolerance to LPS is not induced in macrophages from p50-/- mice; (2) long-term pretreatment with LPS does not block synthe sis of TNF mRNA in p50-/- macrophages (in contrast to wild-type macrop hages); (3) ectopic overexpression of p50 reduces transcriptional acti vation of the murine TNF promoter; and (4) analysis of the four kappa B shes from the murine TNF promoter demonstrates that binding of p50 h omodimers to the positively acting kappa B3 element is associated with development of the LPS-tolerant phenotype. Thus, p50 expression plays a key role in the development of LPS tolerance.