Surfactant protein A increases matrix metalloproteinase-9 production by THP-1 cells.
Matrix metalloproteinase (MMP)-9 from alveolar macrophages is a major source of elastolytic activity in the lung. It is increased in the bronchoalveolar lavage fluid of patients with emphysema. Although the importance of macrophage-derived elastolytic activity in the pathogenesis of emphysema is well established, questions remain about MMP-9 regulation and activity. Because surfactant protein A (SP-A) is capable of modulating other functions of human monocytic cells, we hypothesized that SP-A may regulate MMP-9 expression. Vitamin D3-differentiated THP-1 cells and peripheral blood mononuclear cells were stimulated in vitro with several concentrations of SP-A for different incubation times. MMP-9 mRNA expression was measured by dot-blot analysis, gelatinolytic activity in the medium was determined by gel zymography, protein expression was determined by ELISA, and a specific MMP-9 activity assay was used to measure the state of activation of this enzyme in the cell supernatants. SP-A induced the expression of MMP-9 in both cell types, the effect was time and dose dependent, and MMP-9 was released in its zymogen form. On the basis of results of neutralizing antibody studies, we believe that SP-A action is mediated through Toll-like receptor-2. Even though the biological meaning of these findings remains to be elucidated, these observations suggest the presence of a novel, locally controlled mechanism by which MMP-9 levels may be regulated in alveolar macrophages. We speculate that SP-A may influence the protease/antiprotease balance in the lungs of patients with quantitative and/or qualitative changes in surfactant constituents favoring an abnormal breakdown of extracellular matrix components.
Vazquez de Lara
Luis G
LG
Dept. of Pediatrics, Pennsylvania State Univ. College of Medicine, PO Box 850, Hershey, PA 17033, USA. dsp4@psu.edu
Umstead
Todd M
TM
Davis
Sara E
SE
Phelps
David S
DS
D000906:Antibodies / Q000494:pharmacology; D002478:Cells, Cultured; D003470:Culture Media / Q000378:metabolism; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D008562:Membrane Glycoproteins / Q000276:immunology; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism*; D037662:Pulmonary Surfactant-Associated Protein A / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors
D000906:Antibodies; D003470:Culture Media; D008562:Membrane Glycoproteins; D037662:Pulmonary Surfactant-Associated Protein A; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D020780:Matrix Metalloproteinase 9