Prostaglandin regulation of macrophage collagenase production.

Abstract

The production of collagenase (EC 3.4.24.3) by endotoxin-stimulated macrophages was significantly inhibited by indomethacin, indicating that prostaglandins (PGs) 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 1.0MgM PGE2 increased the enzyme production to 3 times that achieved by endotoxin. Although the addition of prostaglandin alone to macrophage cultures did not stimulate collagenase 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 ,uM.PGF2, had little effect on either the enhancement of collagenase production by endotoxin-stimulated macrophages or its restoration in cultures inhibited by indomethacin. Radioimmunoassay of prostaglandins 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 hr after exposure to endotoxin and was maximal at 14 hr. 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.Certain chronic inflammatory lesions are often accompanied by destruction of connective tissue. Increased levels of collagenase (1-6) and prostaglandins (779) have been identified in many of these lesions. The coexistence of these two components in sites of inflammation suggests that prostaglandins may influence collagenase production. Since we have previously shown that the macrophage, a prominent cell type in chronic inflammatory lesions, can be stimulated by endotoxin (10) or lymphokines (11) to produce collagenase, it was of interest to determine whether prostaglandins were involved in the activation of these cells. Here we report that the elevated levels of prostaglandin E2 (PGE2) produced by endotoxin-stimulated macrophages have a regulatory role in the production of collagenase by these cells. MATERIALS AND METHODSCulture Methods. Macrophages were obtained from mineral oil-induced peritoneal exudates in guinea pig and cultured as described (10). Activation of the macrophages was achieved by the addition of endotoxin (30 ,ug/ml) from Escherichia coli (055:B5 Difco Laboratories, Detroit, MI) to the cultures. Media were harvested daily from the cultures and frozen at -20°until assayed. Prostaglandins E1, E2, and F2a (PGE1, PGE2, and PGF2a) (generously supplied by John Pike, Upjohn Co., Kalamazoo, MI) were dissolved in ethanol and added to the culture The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. (12). One volume of 1 M sodium citrate (pH 3.5) was adde...

Monocyte Membrane Type 1-Matrix Metalloproteinase

“…Therefore, regulation of signal transduction events that are associated with the production of inflammatory mediators, such as MMPs, has been of considerable interest. A PGE 2 -cAMP-dependent pathway leading to the production of MMP-1, MMP-9, and MMP-7 (matrilysin) by activated monocytes has been demonstrated previously (13,16,(23)(24)(25)(26). In the present study, we have demonstrated that LPS induces monocyte MT1-MMP and that the signaling pathway for MT1-MMP synthesis involves, in large part, a PGE 2 -dependent mechanism.…”

“…Effect of PGE 2 on Monocyte MT1-MMP Expression-The induction of MMPs in monocytes by agents such as concanavalin A, LPS, or secreted protein, acidic and rich in cysteine, has been shown to occur through a prostaglandin-dependent pathway (13,16,(23)(24)(25)(26). To determine whether monocyte MT1-MMP production is regulated through this pathway, monocytes were pretreated with indomethacin for 1 h and then stimulated with LPS in the absence or presence of PGE 2 .…”

Participation of monocyte-macrophages and lymphocytes in the production of a factor that stimulates collagenase and prostaglandin release by rheumatoid synovial cells.

“…However, these synovial cells prodtuce prostaglandins, particularly PGE2, in relatively high anuiotiunts. Although PGE2 can modulate collagenase production by rodent macrophages (23), as well as bv huiman rheumatoid synovial cells (24), the amount of PGE2 in the mononuclear cell media used in the present studies cannot account for the observed effects on collagenase production by synovial cells, and monocytes incubated in the presence of indomethacin still release collagenase-stimulating factor (25).…”

Monocytes regulate osteoclast-activating factor production by releasing prostaglandins.

“…Other work from our laboratory has demonstrated that monocytes directly resorb both devitalized bones by a mechanism which is not mediated by the action of osteoclasts (25) and live bones through an osteoclast-mediated mechanism which is prostaglandin-dependent (26). There is also other evidence which suggests that monocytes and macrophages synthesize and release PGs (27)(28)(29), collagenase (30), and hydrolytic enzymes (31), which are all capable of resorbing bone or degrading bone matrix. It is also possible that circulating mononuclear cells may transform or differentiate into osteoclasts (32).…”