Regulation of human peripheral blood monocyte collagenase by prostaglandins and anti-inflammatory drugs.
Macrophages, which produce the collagenolytic enzyme collagenase, are commonly found at sites of connective tissue destruction in chronic inflammatory lesions. Since tissue macrophages are derived from circulating peripheral blood monocytes, we used these less-differentiated, more readily available cells to examine the production and regulation of collagenase. Human monocytes, isolated in large quantities by counterflow centrifugal elutriation, were shown to produce substantial amounts of collagenase when stimulated by concanavalin A (Con A) and to a lesser extent with lipopolysaccharide, while unstimulated monocyte cultures produced negligible collagenase. Collagenase was detected in the culture media within the first 24 hr of culture after activation with peak production at 48 hr. Analysis of the intracellular regulation of collagenase revealed that synthesis of this enzyme required a prostaglandin (PGE2)-dependent step since indomethacin-inhibited enzyme synthesis was reversed by PGE2. Additionally, dibutyryladenosine cyclic monophosphate (dBcAMP) restored collagenase synthesis in indomethacin-blocked cultures, indicating a PGE2-dependent generation of cAMP requirement for collagenase production similar to that demonstrated in experimental animals systems. In additional studies, anti-inflammatory drugs which are known to modulate connective tissue destruction were analyzed for their influence on monocyte-derived collagenase. Dexamethasone, colchicine or retinoic acid all inhibited collagenase synthesis by monocytes in a dose-dependent manner although the effect of these drugs on monocyte PGE2 synthesis differed. Dexamethasone inhibited PGE2 synthesis, which resulted in the suppression of collagenase. However, PGE2 production was unaffected by colchicine whereas retinoic acid caused a significant increase in PGE2 levels. Inhibition of collagenase synthesis by dexamethasone, but not colchicine or retinoic acid, could be reversed by PGE2 or phospholipase A2. These findings provide insight into the intracellular events regulating monocyte collagenase synthesis and also implicate monocytes as a target of anti-inflammatory agents which ameliorate connective tissue degradation associated with chronic inflammatory lesions.
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D003208:Concanavalin A / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D003513:Cycloheximide / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D003012:Microbial Collagenase / Q000096:biosynthesis / Q000097:blood*; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology; D010741:Phospholipases A / Q000502:physiology; D054467:Phospholipases A2; D011453:Prostaglandins / Q000494:pharmacology*; D011458:Prostaglandins E / Q000097:blood / Q000502:physiology
D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D011453:Prostaglandins; D011458:Prostaglandins E; D003208:Concanavalin A; D003907:Dexamethasone; D003094:Collagen; D003513:Cycloheximide; D000242:Cyclic AMP; D010741:Phospholipases A; D054467:Phospholipases A2; D003012:Microbial Collagenase; D015232:Dinoprostone