Comparison of suppressive effects of a new anti-inflammatory compound, FR167653, on production of PGE2 and inflammatory cytokines, human monocytes, and alveolar macrophages in response to endotoxin.

FR167653 E1-C7-(4-fluorophenyl)-1, 2, 3, 4-tetrahydro-8 A4-pyridylB pyrazoro C5-1-cD C1, 2, 4D triazin-2-ylD-2-phenylethanedion sulfate monohydrateF was developed to inhibit proinflammatory cytokine production. However, the effects of FR167653 on prostanoid production are unclear. We investigated the effect of FR167653 on proinflammatory cytokine and prostaglandin APGB production by lipopolysaccharide ALPSB-stimulated human peripheral blood monocytes and alveolar macrophages A MB from the same individuals, and compared the effects in monocytes and AM. FR167653 inhibited interleukin-1b and tumor necrosis factor a production. The effect on PGE2 production was assessed by four parameters. FR167653 inhibited PGE2 synthesis and LPS induction of cyclooxygenase activity. Western and Northern blot analyses revealed that LPS induction of cyclooxygenase-2 expression was attenuated by this compound. The suppression in monocytes was greater than that in AM. We concluded that the reduction of LPSinduced PGE2 synthesis by FR167653 was due to inhibition of cyclooxygenase-2 production. These results show that FR167653 may be therapeutically useful for inhibiting production of both inflammatory cytokines and PG production in inflammatory diseases. J. Leukoc. Biol. 65: 80–86; 1999.