Differential regulation of COX-2 expression in the kidney by lipopolysaccharide: role of CD14

Induction of the inducible cyclooxygenase isoform COX-2 is likely to be an important mechanism for increased prostaglandin production in renal inflamm ation. We examined the effect of lipopolysaccharide (LPS) on regional renal COX-2 expression in the rat. In the inner medulla, LPS injection (4 mg/kg ip) induced a twofold and 2.5-fold increase in the levels of COX-2 mRNA and COX-2 protein, respectively. In contrast, COX-2 expression in the renal co rtex was not significantly altered. COX-2 promoter transgenic mice were cre ated using the 2.7-kb flanking region of the rat COX-2 gene. In these anima ls, LPS injection induced reporter gene expression predominately in the inn er medulla. The LPS receptor CD14, usually regarded as a monocyte/macrophag e specific marker, was found to be abundantly expressed in the inner medull a and in dissected inner medullary collecting duct (IMCD) cells, suggesting that it may mediate medullary COX-2 induction. CD14 was present only at lo w levels in cortex and cortical segments, including glomeruli. Ln cultured cells,it was abundant in mouse IMCD (mIMCD-K2) cells and renal medullary in terstitial cells, but largely undetectable in mesangial cells and M1 cells, a cell line derived from mouse cortical collecting ducts. In the mIMCD-K2 cell Line, LPS significantly induced COX-2 mRNA expression, with concomitan t induction of CD14. LPS-stimulated COX-2 expression was reduced by the add ition of an anti-CD14 monoclonal antibody to the culture medium. These resu lts demonstrate that LPS selectively stimulates COX-2 expression in the ren al inner medulla through a CD14-dependent mechanism.