Prostaglandin regulation of macrophage collagenase production.

Abstract

The production of collagenase (EC 3.4.24.3) by endotoxin-stimulated [guinea pig] macrophages was significantly inhibited by indomethacin, indicating that prostaglandins (PG) mediate this effect. Inhibition of collagenase production by indomethacin was overcome by addition of exogenous PGE2 at 10 nM whereas the addition of 0.1 and 1.0 .mu.M PGE2 increased the enzyme production to 3 times that achieved by endotoxin. Although the addition of PG alone to macrophage cultures did not stimulate collagnease production, the simultaneous addition of PGE1 or PGE2 and endotoxin enhanced collagenase activity 2- to 10-fold. This increase was detectable at PGE concentrations of 10 nM and was optimal at 0.1-1.0 .mu.M. PGF2.alpha. had little effect on either the enhancement of collagenase production by endotoxin-stimulated macrophages or its restoration in cultures inhibited by indomethacin. Radioimmunoassay of PG in the culture media revealed that macrophages exposed to endotoxin secreted 40-fold more PGE2 than did unstimulated cells. The increase in PGE2 was detected 4 h after exposure to endotoxin and was maximal at 14 h. The peak PGE2 concentrations in the culture media were similar to those of exogenous PGE2 (about 10 nM) needed to restore collagenase production in indomethacin-treated cultures. These findings demonstrate the involvement of PGE in the endotoxin-activation of macrophages with resultant production of collagenase.