ROLE OF TUMOR-NECROSIS-FACTOR-ALPHA IN INDUCTION OF MURINE CD14 GENE-EXPRESSION BY LIPOPOLYSACCHARIDE

We previously demonstrated CD14 gene expression in myeloid and epithel ial cells of the mouse and shelved that expression of the CD14 gene in both is modulated by lipopolysaccharide (LPS). sere we test the hypot hesis that the induction of CD14 in these cells is an indirect effect of LPS, one mediated by tumor necrosis factor alpha (TNF-alpha). TNF-a lpha induced a transient increase in levels of CD14 in plasma with a p eak at 6 to 8 h, and this increase in levels of CD14 antigen in plasma was accompanied by increased levels of CD14 mRNA in lung, liver, and kidney. Moreover, in situ hybridization studies revealed that CD14 mRN A was induced in both myeloid cells and epithelial cells, the same cel ls that respond to LPS. Pretreatment of mice,vith anti-TNF antiserum r educed the LPS-mediated increase in levels of CD14 in plasma and signi ficantly reduced the level of induction of CD14 mRNA in selected epith elial cells in the kidney and liver. The antiserum did not appear to b lock LPS-mediated induction in myeloid cells in the tissues examined. In C3H/HeJ mice, the epithelial response to LPS was markedly attenuate d whereas the response to TNF-alpha was normal. Thus, regulation of CD 14 gene expression by LPS differs in epithelial and myeloid cells, wit h the epithelial responses in kidney and liver being mediated, in part , by TNF-alpha.