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Secretion by Fibronectin and Type I Collagen of Human Airway Smooth Multiple β1 Integrins Mediate Enhancement of Human Airway Smooth Muscle Cytokine Secretion by Fibronectin and Type I Collagen This information is current as Qi Peng, Dilys Lai, Trang T.-B. Nguyen, Vivien Chan, of September 27, 2021. Takeshi Matsuda and Stuart J. Hirst J Immunol 2005; 174:2258-2264; ; doi: 10.4049/jimmunol.174.4.2258 http://www.jimmunol.org/content/174/4/2258 Downloaded from References This article cites 33 articles, 6 of which you can access for free at: http://www.jimmunol.org/content/174/4/2258.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 27, 2021 *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 © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology ␤ Multiple 1 Integrins Mediate Enhancement of Human Airway Smooth Muscle Cytokine Secretion by Fibronectin and Type I Collagen1 Qi Peng,2 Dilys Lai,2 Trang T.-B. Nguyen, Vivien Chan, Takeshi Matsuda, and Stuart J. Hirst3 Altered airway smooth muscle (ASM) function and enrichment of the extracellular matrix (ECM) with interstitial collagen and fibronectin are major pathological features of airway remodeling in asthma. We have previously shown that these ECM compo- nents confer enhanced ASM proliferation in vitro, but their action on its newly characterized secretory function is unknown. Here, we examined the effects of fibronectin and collagen types I, III, and V on IL-1␤-dependent secretory responses of human ASM cells, and characterized the involvement of specific integrins. Cytokine production (eotaxin, RANTES, and GM-CSF) was eval- uated by ELISA, RT-PCR, and flow cytometry. Function-blocking integrin mAbs and RGD (Arg-Gly-Asp)-blocking peptides were Downloaded from used to identify integrin involvement. IL-1␤-dependent release of eotaxin, RANTES, and GM-CSF was enhanced by fibronectin and by fibrillar and monomeric type I collagen, with similar changes in mRNA abundance. Collagen types III and V had no effect on eotaxin or RANTES release but did modulate GM-CSF. Analogous changes in intracellular cytokine accumulation were found, ␣ ␤ ␣ ␤ ␣ ␤ but in <25% of the total ASM cell population. Function-blocking Ab and RGD peptide studies revealed that 2 1, 5 1, v 1, ␣ ␤ ␤ ␣ ␤ and v 3 integrins were required for up-regulation of IL-1 -dependent ASM secretory responses by fibronectin, while 2 1 was ␤ an important transducer for type I collagen. Thus, fibronectin and type I collagen enhance IL-1 -dependent ASM secretory http://www.jimmunol.org/ ␤ responses through a 1 integrin-dependent mechanism. Enhancement of cytokine release from ASM by these ECM components may contribute to airway wall inflammation and remodeling in asthma. The Journal of Immunology, 2005, 174: 2258–2264. hronic asthma is characterized by poorly reversible air- logic studies of asthmatic airways have revealed abnormalities in way obstruction and airway hyperresponsiveness that is both the quantity and composition of ECM proteins. Collagen C associated with intense persistent inflammation and types I, III, and V; fibronectin; tenascin; hyaluronan; versican; and ␣ ␤ structural remodeling of the airway wall (1, 2). Two prominent laminin 2/ 2 chains are increased, whereas other major ECM features of the remodeling process that may underlie or contribute components including collagen type IV and elastin are decreased to the development of airways hyperresponsiveness in asthmatics (5–9). Increased type I collagen, hyaluronan, and versican have by guest on September 27, 2021 4 include accumulation of airway smooth muscle (ASM), possibly been found localized within and surrounding ASM bundles from due to hyperplastic and/or hypertrophic changes (3, 4) and alter- asthmatics (9, 15). In the bronchoalveolar lavage fluid of asthmat- ations in the amount and composition extracellular matrix (ECM) ics, increased levels of fibronectin, hyaluronan, and laminin prod- proteins (5–9). In addition to ASM accumulation in asthma, evi- ucts are found (reflecting increased ECM turnover), which corre- dence suggests that ASM may contribute to airway wall inflam- late with asthma severity (16). These studies support marked ECM matory events by expressing cell adhesion receptors and costimu- changes in the airway wall in asthma. However, little is known of latory molecules, and by releasing multiple cytokines and the impact of enrichment of the airway wall with collagen and chemokines including those which activate eosinophils such as fibronectin on airway cell function. eotaxin, RANTES, and GM-CSF (10–13). Previously, we have reported that both fibronectin and type I ECM proteins ligating via cell surface integrin ECM receptors collagen enhance responses of cultured human ASM cells to mi- regulate diverse cellular functions including growth, migration, ␣ survival, and the maintenance of differentiated status (14). Histo- togens such as PDGF-BB and -thrombin (17). Bonacci et al. (18) report similar findings with fibroblast growth factor-2-dependent proliferation of bovine tracheal smooth muscle cultured on type I Department of Asthma, Allergy and Respiratory Science, The Guy’s, King’s and St. collagen; and Freyer et al. (19) have shown that both type I col- Thomas’ School of Medicine, King’s College London, Guy’s Hospital Campus, Lon- don, United Kingdom lagen and fibronectin increase survival of human ASM cells. More- Received for publication August 18, 2004. Accepted for publication November over, ASM cells cultured from asthmatic individuals or grown on 16, 2004. homologous ECM from asthmatic ASM cells proliferate more rapidly The costs of publication of this article were defrayed in part by the payment of page (20). Collectively, these observations affirm that ASM in situ likely is charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. subjected to the influences of signaling through ECM/integrin inter- 1 This study was supported by Asthma U.K. (no. 00/44), the Special Trustees of Guy’s actions, and have led to the suggestion that alterations in airway wall and St. Thomas’ Hospitals, and the Wellcome Trust (no. 051435). ECM microenvironment in remodeling in asthma may favor en- 2 Q.P. and D.L. contributed equally to this work. hanced survival and growth responses of ASM during inflammation 3 Address correspondence and reprint requests to Dr. Stuart J. Hirst, Department of (17–19). However, it is unknown whether the ECM has analogous Asthma, Allergy and Respiratory Science, The Guy’s, King’s and St. Thomas’ School effects on ASM secretory responses. of Medicine, Thomas Guy House, Guy’s Hospital Campus, London, U.K. SE1 9RT. E-mail address: [email protected] In the present study, we hypothesized that enrichment of the 4 Abbreviations used in this paper: ASM, airway smooth muscle; ECM, extracellular airway wall ECM environment with fibronectin and type I colla- matrix; Pl, plastic. gen, as occurs in asthma, confers increased secretory properties of Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 The Journal of Immunology 2259 ASM. We compared IL-1␤/TNF-␣-dependent eosinophil-activat- sciences) (22). After analysis, cells were confirmed microscopically to be ing cytokine release from human ASM cells that were cultured intact. either on plastic (Pl) or fibronectin or on varying forms of collagen. Measurement of cytokine levels by ELISA Moreover, we characterized the integrin heterodimer subunits ex- pressed by ASM and their involvement in modulating secretory Levels of eotaxin, RANTES, and GM-CSF were determined in duplicate in responses. the same samples of cell-conditioned medium by specific sandwich ELISA as described previously (13). Manual cell counts were repeated after col- lection of cell-conditioned medium to confirm numbers were unchanged Materials and Methods after stimulation, and to allow cytokine levels to be expressed initially in Isolation and culture of human ASM cells nanograms per milliliter per million cells before normalization for stimu- lation on Pl to correct for small variations in release between cell lines. Human ASM cells were obtained in accordance with procedures approved by the Guy’s and St. Thomas’ Hospitals’ Research Ethics Committee from RT-PCR the lobar or main bronchus of 45 nonasthmatic patients (mean age, 64 Ϯ 4 years; range, 28–78 years; 24 male, 21 female) undergoing lung resection Total RNA was isolated using the RNeasy mini kit (Qiagen), and its con- for carcinoma of the bronchus using methods described previously (13). centration was determined using the RiboGreen RNA quantification kit Fluorescent immunocytochemical and flow cytometric techniques con- (Molecular Probes). Full-length first-strand cDNA was synthesized using 2 ␮ ␮ firmed that near-confluent, FBS-deprived human ASM cells (passage 2) g of total RNA in a 33- l reverse transcriptase reaction mixture with stained (Ͼ95%) for smooth muscle-specific ␣-actin and calponin (17). Ready-To-Go You-Prime beads and random hexamer primers (Amersham Cells at passages 3–5 were used in all experiments. Biosciences) as previously described (22). To confirm PCR were per- formed within the linear for amplification, the number of cycles was ini- tially varied from 20 to 28. The size of the amplicons corresponded to Surface coating with ECM proteins Downloaded from predicted sizes (eotaxin, 182 bp; RANTES, 332 bp; GM-CSF, 277 bp), Lyophilized human plasma fibronectin (Sigma-Aldrich), rat monomeric confirmed by sequencing.
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