DIFFERENTIAL REGULATION OF METALLOELASTASE ACTIVITY IN MURINE PERITONEAL-MACROPHAGES BY GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR AND MACROPHAGE-COLONY-STIMULATING FACTOR

We investigated the regulation of elastase activity in murine peritone al macrophages by different cytokines and bacterial LPS. Thioglycolate -elicited mouse peritoneal exudate macrophages secrete a metalloprotei nase that degrades elastin. Incubation of : peritoneal exudate macroph ages with LPS: and IFN-gamma significantly inhibited the production of elastase by a mechanism independent of nitric oxide, superoxide, and hydrogen peroxide. The cytokines IL-1 alpha; IL-1 beta, IL-2, IL-4, IL -6, IL-8, IL-10, TNF, TGF-alpha and -beta, basic fibroblast growth fac tor, monocyte chemotactic factor-1, and granulocyte CSF (G-CSF) had no significant effect on the production of elastase by macrophages. In c ontrast, granulocyte-macrophage CSF (GM-CSF) increased the production of elastase in a dose-dependent manner, and with macrophage CSF (M-CSF ) inhibited it. Elastin zymography demonstrated that the modulation of elastolytic activity in macrophages was associated with changes in th e level of metalloelastase protein. The stimulation of elastase activi ty by GM-CSF and the inhibition of elastase activity by LPS, IFN-gamma , and M-CSF occurred at the level of transcription. LPS and M-CSF also augmented the expression level of tissue Inhibitors of metalloprotein ase mRNA, The increased mRNA steady state level Of murine macrophage e lastase induced by GM-CSF resulted from both increased transcription a nd enhanced stability, The modulation of metalloelastase activity in m acrophages by IFN-gamma, M-CSF, and GM-CSF suggests that these molecul es may control the degradation of elastin fibers in lungs or blood ves sels.