title: Membrane-bound matrix metalloproteinase-8 on activated polymorphonuclear cells is a potent, tissue inhibitor of metalloproteinase-resistant collagenase and serpinase.
abstract: Little is known about the cell biology or the biologic roles of polymorphonuclear cell (PMN)-derived matrix metalloproteinase-8 (MMP-8). When activated with proinflammatory mediators, human PMN release only approximately 15-20% of their content of MMP-8 ( approximately 60 ng/10(6) cells) exclusively as latent pro-MMP-8. However, activated PMN incubated on type I collagen are associated with pericellular collagenase activity even when bathed in serum. PMN pericellular collagenase activity is attributable to membrane-bound MMP-8 because: 1) MMP-8 is expressed in an inducible manner in both pro- and active forms on the surface of human PMN; 2) studies of activated PMN from mice genetically deficient in MMP-8 (MMP-8(-/-)) vs wild-type (WT) mice show that membrane-bound MMP-8 accounts for 92% of the MMP-mediated, PMN surface type I collagenase activity; and 3) human membrane-bound MMP-8 on PMN cleaves types I and II collagens, and alpha(1)-proteinase inhibitor, but is substantially resistant to inhibition by tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2. Binding of MMP-8 to the PMN surface promotes its stability because soluble MMP-8 has t(1/2) = 7.5 h at 37 degrees C, but membrane-bound MMP-8 retains >80% of its activity after incubation at 37 degrees C for 18 h. Studies of MMP-8(-/-) vs WT mice given intratracheal LPS demonstrate that 24 h after intratracheal LPS, MMP-8(-/-) mice have 2-fold greater accumulation of PMN in the alveolar space than WT mice. Thus, MMP-8 has an unexpected, anti-inflammatory role during acute lung injury in mice. TIMP-resistant, active MMP-8 expressed on the surface of activated PMN is likely to be an important form of MMP-8, regulating lung inflammation and collagen turnover in vivo.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, 905 Thorn Building, 75 Francis Street, Boston, MA 02115, USA. cowen@rics.twh.harvard.edu
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Owen
authors.forename: Zhuma
authors.initials: Z
authors.lastname: Hu
authors.forename: Carlos
authors.initials: C
authors.lastname: Lopez-Otin
authors.forename: Steven D
authors.initials: SD
authors.lastname: Shapiro
mesh_terms: D000818:Animals; D002384:Catalysis; D002478:Cells, Cultured; D017364:Collagenases / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators; D008070:Lipopolysaccharides / Q000494:pharmacology; D020784:Matrix Metalloproteinase 8 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018375:Neutrophil Activation; D009504:Neutrophils / Q000201:enzymology*; D012128:Respiratory Distress Syndrome / Q000201:enzymology; D015843:Serpins / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism*
chemical_list: D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D015843:Serpins; D019714:Tissue Inhibitor of Metalloproteinases; D017364:Collagenases; D020784:Matrix Metalloproteinase 8