Synergistic and selective stimulation of gelatinase B production in macrophages by lipopolysaccharide, trans-retinoic acid and CGP 41251, a protein kinase C regulator.
The production of gelatinase B by macrophages is relevant in the immunological and migratory functions of macrophages. CGP 41251, an inhibitor of protein kinase C (PKC), was found to stimulate the expression of gelatinase B in macrophages, as shown by the study of two different monocytic/macrophagic cell lines, mouse RAW 264.7 and human THP-1 cells. When human monocytes and rat peritoneal macrophages were treated with CGP 41251, insignificant increases of 10 and 25% were obtained. This can possibly be due to the presence of contaminating cells in these two enriched populations, since the CGP 41251 treatment of non-macrophagic cell lines inhibited their PMA-induced gelatinase B production. Taken together, these results suggest that the stimulatory effect of CGP 41251 is specific to cells of the monocytic lineage. Using RAW 264.7 cells as a model, the effect of CGP 41251 is additive to that obtained using lipopolysaccharide (LPS) and phorbol 12-myristate 13-acetate (PMA), as revealed by gelatin zymography and Northern blot analysis. The stimulatory effect of CGP 41251 on gelatinase B production in RAW 264.7 was: (a) inhibited by calphostin C (as is the LPS-induced response), indicating a PKC-dependence; (b) inhibited by dexamethasone (as opposed to the LPS-induced response); and (c) enhanced by addition of trans-retinoic acid (RA). In fact, RA can induce gelatinase B production, either alone or in synergy with LPS and/or CGP 41251, since the combination of the three agents gives the highest gelatinase B response, at both the protein and the mRNA levels. This represents an important observation considering the RA is now being tested as an anti-cancer agent and proposed for prevention studies.
Houde
M
M
Institut Armand-Frappier, Centre de Recherches en Immunologie, Québec, Canada.
Tremblay
P
P
Masure
S
S
Opdenakker
G
G
Oth
D
D
Mandeville
R
R
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D017364:Collagenases / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology*; D020780:Matrix Metalloproteinase 9; D008969:Molecular Sequence Data; D011493:Protein Kinase C / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D012045:Regulatory Sequences, Nucleic Acid; D019311:Staurosporine / Q000031:analogs & derivatives*; D014212:Tretinoin / Q000494:pharmacology; D015854:Up-Regulation
D000470:Alkaloids; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014212:Tretinoin; D011493:Protein Kinase C; D017364:Collagenases; D020780:Matrix Metalloproteinase 9; D019311:Staurosporine; C059539:midostaurin