Dexamethasone selectively modulates basal and lipopolysaccharide-induced metalloproteinase and tissue inhibitor of metalloproteinase production by human alveolar macrophages.
To define the capacity of glucocorticoids to regulate tissue damage associated with inflammation more clearly, we have studied the effects of dexamethasone on human alveolar macrophage secretion of both a variety of metalloproteinases and also the counter-regulatory tissue inhibitor of metalloproteinases (TIMP). We found that dexamethasone selectively and coordinately inhibited expression of the following human metalloproteinases: interstitial collagenase, stromelysin, and the 92-kDa type IV collagenase, as well as TIMP. Both basal and LPS-stimulated cells exhibited similar degrees of inhibition, with greater than 50% decrease in secretion of all enzymes and TIMP observed at dexamethasone concentrations of greater than or equal to 10(-8) M in serum-containing medium. The effects of dexamethasone were mediated at a pretranslational level. In summary, our results indicate that glucocorticoids suppress the matrix-degrading phenotype that is characteristic of mature human mononuclear phagocytes, and block the effects of the most potent known signal for upregulation of metalloproteinase secretion. Similar actions in vivo would serve to limit tissue damage associated with the inflammatory response.
Shapiro
S D
SD
Department of Medicine, Jewish Hospital, Washington University Medical Center, St. Louis, MO 63110.
Campbell
E J
EJ
Kobayashi
D K
DK
Welgus
H G
HG
D015152:Blotting, Northern; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006023:Glycoproteins / Q000096:biosynthesis*; D006801:Humans; D066298:In Vitro Techniques; D008070:Lipopolysaccharides; D008264:Macrophages / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases / Q000096:biosynthesis*; D003012:Microbial Collagenase / Q000096:biosynthesis; D014176:Protein Biosynthesis; D012313:RNA / Q000032:analysis; D013997:Time Factors; D019714:Tissue Inhibitor of Metalloproteinases; D015854:Up-Regulation
D006023:Glycoproteins; D008070:Lipopolysaccharides; D019714:Tissue Inhibitor of Metalloproteinases; D012313:RNA; D003907:Dexamethasone; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D003012:Microbial Collagenase