title: A site on laminin alpha 5, AQARSAASKVKVSMKF, induces inflammatory cell production of matrix metalloproteinase-9 and chemotaxis.
abstract: Several peptide sequences in laminin alpha1, the alpha-chain of laminin (Ln)-1, mediate biological responses in vitro, but Ln-1 is rare in vivo. Since Ln-5 and Ln-10, which contain the alpha3 and alpha5 chains, respectively, are the most prominent laminin heterotrimers in normal adult tissues and few functional domains in other laminin chains have been identified, we are investigating the alpha3 and alpha5 chains for biological activities. Incubation of mouse macrophages with the laminin alpha5 peptide AQARSAASKVKVSMKF resulted in marked increase in matrix metalloproteinase (MMP)-9 mRNA and gelatinolytic activity in the conditioned media, whereas the corresponding alpha3 peptide QQARDAANKVAIPMRF had no effect. AQARSAASKVKVSMKF also induced expression of MMP-14, while MMP-2, MMP-3, MMP-7, MMP-12, and MMP-13 were not induced by this peptide. Deletion analyses indicated that a minimal sequence of ASKVKVSMKF was sufficient for increasing MMP-9 expression. AQARSAASKVKVSMKF was also chemotactic for neutrophils and macrophages in vitro, and induced accumulation of neutrophils and macrophages in lung airspaces in vivo following intranasal instillation into mice. Comparable accumulation occurred in MMP-9-deficient mice, indicating that MMP-9 was not required for AQARSAASKVKVSMKF-induced inflammatory cell emigration in the lung. A scrambled version of the minimal peptide, KAKSFVMVSK, was inactive. These data indicate that laminin alpha5-derived peptides can induce inflammatory cell chemotaxis and metalloproteinase activity.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine and Barnes-Jewish Hospital, St. Louis, MO 63110, USA.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Adair-Kirk
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Atkinson
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Broekelmann
authors.forename: Masayuki
authors.initials: M
authors.lastname: Doi
authors.forename: Karl
authors.initials: K
authors.lastname: Tryggvason
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Miner
authors.forename: Robert P
authors.initials: RP
authors.lastname: Mecham
authors.forename: Robert M
authors.initials: RM
authors.lastname: Senior
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000502:physiology*; D017124:Conserved Sequence; D004790:Enzyme Induction / Q000235:genetics / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D007797:Laminin / Q000737:chemistry / Q000502:physiology*; D008264:Macrophages / Q000201:enzymology* / Q000473:pathology / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000172:deficiency / Q000378:metabolism; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000096:biosynthesis / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009000:Monocytes / Q000201:enzymology / Q000502:physiology; D009504:Neutrophils / Q000201:enzymology* / Q000473:pathology / Q000502:physiology; D010446:Peptide Fragments / Q000737:chemistry / Q000502:physiology*; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology
chemical_list: D007797:Laminin; D010446:Peptide Fragments; C097043:laminin alpha5; C084098:laminin A; C095567:laminin alpha 3; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020780:Matrix Metalloproteinase 9