Recombinant murine interleukin-1β (IL-1β) induced a transient increase in plasma levels of CD14 with a peak at 8 h, and this increase in plasma CD14 antigen was accompanied by increased levels of CD14 messenger ribonucleic acid (mRNA) in all organs examined. In most organs, maximal levels of induction were obtained after administration of 125 ng of IL-1β. Moreover, in situ hybridization studies revealed that CD14 mRNA was induced in both myeloid cells and epithelial cells. Pretreatment of mice with anti-IL-1β antibodies reduced the subsequent induction of plasma levels of CD14 by lipopolysaccharide (LPS) and significantly reduced the level of induction of CD14 mRNA in kidney and liver. The antibodies did not block LPS mediated induction in lung. Pretreatment with a combination of anti-IL-1β and anti-tumor necrosis factor (TNF) antibodies was more effective in reducing LPS mediated induction of plasma CD14 and CD14 mRNA in liver than pretreatment with either antibody alone. The combination of anti-IL-1β and anti-TNF antibodies had no additional effect in kidney and lung over that observed with anti-TNF alone. These studies demonstrate that regulation of CD14 gene expression by LPS in vivo involves multiple signals but is mediated, in part, by the cytokines IL-1β and TNF-α.