Macrolide antibiotics promote the LPS-induced upregulation of prostaglandin E receptor EP2 and thus attenuate macrolide suppression of IL-6 production.

We studied the influence of the inhibitory effect of clarithromycin (CAM) and erythromycin (EM) on the production of macrophage inflammatory protein (MIP)-2, interleukin-6 (IL-6), and prostaglandin E(2) (PGE(2)), as well as PGE(2) receptor (EP(2)) expression, by LPS-stimulated RAW264.7 cells. Production of IL-6 was significantly decreased by treatment with CAM or EM in a dose-dependent manner, but the inhibitory effect of CAM was significantly weaker than that of EM. In contrast, the production of MIP-2 and PGE(2) was inhibited to the same extent by CAM and EM. LPS induced the expression of EP(2) mRNA and its expression was promoted further by treatment with CAM or EM. In particular, CAM significantly upregulated EP(2) mRNA expression compared with that after stimulation by LPS alone. After treatment with a nonselective cyclooxygenase (COX) inhibitor (indomethacin), a selective COX-2 inhibitor (NS398), or an EP(2)/EP(4) receptor antagonist (AH6809), the inhibitory effect of CAM and EM on LPS-induced IL-6 production was equalized. These results indicate that macrolide antibiotics upregulate the expression of EP(2), which then attenuates the suppressive effect on IL-6 production of these antibiotics, suggesting that these drugs have a variable anti-inflammatory effect that could influence host defenses.