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Metalloproteinase-9 and Chemotaxis Inflammatory Cell Production of Matrix AQARSAASKVKVSMKF, Induces 5, Α a Site on Laminin

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Metalloproteinase-9 and Chemotaxis Inflammatory Cell Production of Matrix AQARSAASKVKVSMKF, Induces 5, Α a Site on Laminin A Site on Laminin α5, AQARSAASKVKVSMKF, Induces Inflammatory Cell Production of Matrix Metalloproteinase-9 and Chemotaxis This information is current as of September 25, 2021. Tracy L. Adair-Kirk, Jeffrey J. Atkinson, Thomas J. Broekelmann, Masayuki Doi, Karl Tryggvason, Jeffrey H. Miner, Robert P. Mecham and Robert M. Senior J Immunol 2003; 171:398-406; ; doi: 10.4049/jimmunol.171.1.398 Downloaded from http://www.jimmunol.org/content/171/1/398 References This article cites 64 articles, 24 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/171/1/398.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 25, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2003 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology A Site on Laminin ␣5, AQARSAASKVKVSMKF, Induces Inflammatory Cell Production of Matrix Metalloproteinase-9 and Chemotaxis1 Tracy L. Adair-Kirk,* Jeffrey J. Atkinson,* Thomas J. Broekelmann,‡ Masayuki Doi,§ Karl Tryggvason,§ Jeffrey H. Miner,†‡ Robert P. Mecham,*‡ and Robert M. Senior2*‡ Several peptide sequences in laminin ␣1, the ␣-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 ␣3 and ␣5 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 ␣3 and ␣5 chains for biological activities. Incubation of mouse macrophages with the laminin ␣5 peptide AQARSAASKVKVSMKF resulted in marked increase in matrix metalloproteinase (MMP)-9 mRNA and gelatinolytic activity in the conditioned media, whereas the Downloaded from corresponding ␣3 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 che- motactic 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 http://www.jimmunol.org/ of the minimal peptide, KAKSFVMVSK, was inactive. These data indicate that laminin ␣5-derived peptides can induce inflam- matory cell chemotaxis and metalloproteinase activity. The Journal of Immunology, 2003, 171: 398–406. nflammatory cells are recruited to sites of tissue injury by characteristic heterotrimeric structures (2, 3). The long arms of the cell-derived and exogenous chemotactic factors and/or de- three chains associate and form a helical coiled-coil region. The I graded extracellular matrix (ECM)3 components. Once at the C-termini of ␣-chains are unique in that they form a large globular site, inflammatory cells play a role in the extent of tissue remod- structure termed the G-domain. To date, five ␣, three ␤, and three eling, in part, by the regulated production of a family of matrix ␥ laminin chains have been identified, which assemble into at least by guest on September 25, 2021 metalloproteinases (MMPs). MMPs are thought to be involved in fifteen laminin isoforms. The best-characterized laminin is Laminin proteolysis of ECM proteins such as laminins, exposing cryptic (Ln)-1, which has an ␣1, ␤1, ␥1 chain composition (4). Ln-1 pro- domains which can regulate cell adhesion, chemotaxis, and other motes cell adhesion, polarization, migration, and epithelial cell dif- cellular responses. MMPs are important molecules in the regula- ferentiation. Several sites on the Ln-1 molecule that mediate various tion of cell and tumor growth, wound healing, apoptosis, angio- biological responses have been identified at the peptide level (5–12). genesis, tumor invasion, and the immune response (1). Dysregu- It has been proposed that Ln-1 contains cryptic domains, potentially lation of MMP production has been implicated in diverse exposed during proteolysis, which elicit biological responses distinct inflammatory diseases and neoplastic diseases. from the intact Ln-1 molecule (9). Peptides containing the sequence Laminins are a family of integral basement membrane glycop- SIKVAV located near the C-terminal globular domain of the laminin ␣ ␤ ␥ roteins, each containing an -, -, and -chain that assemble into ␣1 chain induce expression of gelatinase B (gelB/MMP-9) by mono- cytes/macrophages (6, 8), whereas intact Ln-1 does not (9). The bi- Divisions of *Pulmonary and Critical Care Medicine and †Renal Diseases, Depart- ologic importance of cryptic domains in the Ln-1 in vivo is unclear ment of Medicine and ‡Department of Cell Biology and Physiology, Washington because laminin ␣1, the ␣-chain of Ln-1, is not expressed in most University School of Medicine and Barnes-Jewish Hospital, St. Louis, MO 63110; and §Division of Matrix Biology, Department of Medical Biochemistry and Biophys- adult tissues (13–18). This suggests that the laminin in the adult ma- ics, Karolinska Institutet, Stockholm, Sweden trix that regulates biological activities likely contains a different lami- Received for publication July 30, 2002. Accepted for publication April 24, 2003. nin ␣-chain. However, few specific sites on other laminin chains have The costs of publication of this article were defrayed in part by the payment of page been identified to promote biological functions. charges. This article must therefore be hereby marked advertisement in accordance Immunohistochemical data indicate that Ln-5 (␣3␤3␥2) and with 18 U.S.C. Section 1734 solely to indicate this fact. ␣ ␤ ␥ 1 Ln-10 ( 5 1 1) are the most prominent Ln heterotrimers in nor- This work was supported by National Institutes of Health, National Heart, Lung, and ␣ Blood Institute, HL29594 and HL47328, the Alan A. and Edith L. Wolff Charitable mal adult tissues (19–23). Therefore, we are investigating the 3 Trust (to R.M.S.), and National Institutes of Health, 5T32 HL07317-24 (to T.L.A.K.), and ␣5 chains for biological activities. In the present work, we and a Research Fellowship from the American Lung Association (to J.J.A.), and ␣ grants from the Novo Nordisc Foundation, the Swedish Medical Research Council, demonstrate that a synthetic laminin 5 chain peptide (AQAR- and European Community Contract QLK3-CT2000-00084 (to K.T.). SAASKVKVSMKF), derived from the corresponding region of 2 Address correspondence and reprint requests to Dr. Robert M. Senior, Department laminin ␣1 that contains the cryptic SIKVAV sequence, has the of Medicine, Barnes-Jewish Hospital, North Campus, 216 South Kingshighway Bou- capacity to increase MMP-9 production by macrophages. In con- levard, St. Louis, MO 63110. E-mail address: [email protected] trast, a peptide from the corresponding region of the laminin ␣3 3 Abbreviations used in this paper: ECM, extracellular matrix; Ln, laminin; MMP, matrix metalloproteinase; MSFM, macrophage serum-free media; PMN, polymor- chain (QQARDAANKVAIPMRF) does not. Furthermore, AQAR- phonuclear neutrophil; BAL, bronchoalveolar lavage. SAASKVKVSMKF promotes MMP-9 release by neutrophils and Copyright © 2003 by The American Association of Immunologists, Inc. 0022-1767/03/$02.00 The Journal of Immunology 399 is chemotactic for inflammatory cells in vitro and in vivo. These MMP-2, MMP-3, MMP-7, MMP-9, MMP-12, MMP-13, MMP-14, and data indicate that laminin ␣5-derived peptides can mediate re- GAPDH, respectively. The resulting amplification products were electro- sponses by inflammatory cells and suggests that laminins contain- phoresed on a 1% agarose gel and stained with ethidium bromide. ing the ␣5 chain (Ln-10 and Ln-11) are likely laminins in the adult Animal treatment matrix that regulate these activities. Six to 8-wk-old 129 SvEv mice (Taconic Farm, Germantown, NY) were housed in a barrier animal facility under the veterinary care of the Depart- Materials and Methods ment of Comparative Medicine at Washington University School of Med- Synthetic laminin peptide icine in accordance with the Animal Welfare Act and the Guide for the Care and Use of Laboratory Animals. Mice were anesthetized by i.p. in- ␤ The synthetic peptide derived from the laminin 1 chain (YIGSR) and the jection of 0.1 ml mouse mixture with each mouse receiving 87 mg/kg intact Ln-1 isolated from the Engelbreth-Holm-Swarm tumor were obtained ketamine HCl (Fort Dodge Laboratories, Fort Dodge, IA) and 13 mg/kg from Sigma-Aldrich (St. Louis, MO). Intact Ln-10 was isolated from HEK293 xylazine HCl (Phoenix Pharmaceuticals, St. Joseph, MO). Euthanasia was ␣ ␤ cells transfected with full-length cDNAs encoding
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