{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:46:20Z","timestamp":1779237980239,"version":"3.51.4"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2014,12,1]],"date-time":"2014-12-01T00:00:00Z","timestamp":1417392000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,12,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Activated neutrophils, recruited to the airway of diseased lung, release human neutrophil peptides (HNP1\u20134) that are cytotoxic to airway cells as well as microbes. Airway epithelial cells express arginine-specific ADP ribosyltransferase (ART)-1, a GPI-anchored ART that transfers ADP-ribose from NAD to arginines 14 and 24 of HNP-1. We previously reported that ADP-ribosyl-arginine is converted nonenzymatically to ornithine and that ADP-ribosylated HNP-1 and ADP-ribosyl-HNP-(ornithine) were isolated from bronchoalveolar lavage fluid of a patient with idiopathic pulmonary fibrosis, indicating that these reactions occur in vivo. To determine effects of HNP-ornithine on the airway, three analogs of HNP-1, HNP-(R14orn), HNP-(R24orn), and HNP-(R14,24orn), were tested for their activity against Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus; their cytotoxic effects on A549, NCI-H441, small airway epithelial-like cells, and normal human lung fibroblasts; and their ability to stimulate IL-8 and TGF-\u03b21 release from A549 cells, and to serve as ART1 substrates. HNP and the three analogs had similar effects on IL-8 and TGF-\u03b21 release from A549 cells and were all cytotoxic for small airway epithelial cells, NCI-H441, and normal human lung fibroblasts. HNP-(R14,24orn), when compared with HNP-1 and HNP-1 with a single ornithine substitution for arginine 14 or 24, exhibited reduced cytotoxicity, but it enhanced proliferation of A549 cells and had antibacterial activity. Thus, arginines 14 and 24, which can be ADP ribosylated by ART1, are critical to the regulation of the cytotoxic and antibacterial effects of HNP-1. The HNP analog, HNP-(R14,24orn), lacks the epithelial cell cytotoxicity of HNP-1, but partially retains its antibacterial activity and thus may have clinical applications in airway disease.<\/jats:p>","DOI":"10.4049\/jimmunol.1303068","type":"journal-article","created":{"date-parts":[[2014,11,13]],"date-time":"2014-11-13T04:24:01Z","timestamp":1415852641000},"page":"6144-6151","source":"Crossref","is-referenced-by-count":7,"title":["Nonenzymatic Conversion of ADP-Ribosylated Arginines to Ornithine Alters the Biological Activities of Human Neutrophil Peptide-1"],"prefix":"10.1093","volume":"193","author":[{"given":"Linda A","family":"Stevens","sequence":"first","affiliation":[{"name":"Cardiovascular and Pulmonary Branch, National, Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph T","family":"Barbieri","sequence":"additional","affiliation":[{"name":"Microbiology and Molecular Genetics, Medical College of Wisconsin , Milwaukee, WI 53226"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Grzegorz","family":"Piszczek","sequence":"additional","affiliation":[{"name":"Biophysics Core Facility, National, Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amy N","family":"Otuonye","sequence":"additional","affiliation":[{"name":"Cardiovascular and Pulmonary Branch, National, Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rodney L","family":"Levine","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry, National, Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gang","family":"Zheng","sequence":"additional","affiliation":[{"name":"Office of Biostatistics Research, National, Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joel","family":"Moss","sequence":"additional","affiliation":[{"name":"Cardiovascular and Pulmonary Branch, National, Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2014,12,15]]},"reference":[{"key":"2025030707501490600_r1","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1615\/CritRevImmunol.v28.i3.10","article-title":"Neutrophil-derived defensins as modulators of innate immune function","volume":"28","author":"Rehaume","year":"2008","journal-title":"Crit. Rev. Immunol."},{"key":"2025030707501490600_r2","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1080\/07853890252953482","article-title":"Role of defensins in inflammatory lung disease","volume":"34","author":"Aarbiou","year":"2002","journal-title":"Ann. Med."},{"key":"2025030707501490600_r3","doi-asserted-by":"crossref","first-page":"6603","DOI":"10.1111\/j.1742-4658.2009.07370.x","article-title":"Alpha-defensins increase lung fibroblast proliferation and collagen synthesis via the beta-catenin signaling pathway","volume":"276","author":"Han","year":"2009","journal-title":"FEBS J."},{"key":"2025030707501490600_r4","doi-asserted-by":"crossref","first-page":"411","DOI":"10.3109\/01902141003714049","article-title":"Differential effects of human neutrophil peptide-1 on growth factor and interleukin-8 production by human lung fibroblasts and epithelial cells","volume":"36","author":"Amenomori","year":"2010","journal-title":"Exp. Lung Res."},{"key":"2025030707501490600_r5","first-page":"L888","article-title":"Effect of defensins on interleukin-8 synthesis in airway epithelial cells","volume":"272","author":"Van Wetering","year":"1997","journal-title":"Am. J. Physiol."},{"key":"2025030707501490600_r6","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1165\/rcmb.2002-0267OC","article-title":"Neutrophil defensins enhance lung epithelial wound closure and mucin gene expression in vitro","volume":"30","author":"Aarbiou","year":"2004","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"2025030707501490600_r7","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1159\/000086651","article-title":"Antimicrobial peptides in lung inflammation","volume":"86","author":"Beisswenger","year":"2005","journal-title":"Chem. Immunol. Allergy"},{"key":"2025030707501490600_r8","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1165\/rcmb.2008-0348TR","article-title":"Transepithelial migration of neutrophils: mechanisms and implications for acute lung injury","volume":"40","author":"Zemans","year":"2009","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"2025030707501490600_r9","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1189\/jlb.0604367","article-title":"Interactions between neutrophil-derived antimicrobial peptides and airway epithelial cells","volume":"77","author":"van Wetering","year":"2005","journal-title":"J. Leukoc. Biol."},{"key":"2025030707501490600_r10","doi-asserted-by":"crossref","first-page":"35","DOI":"10.2174\/1389203053027494","article-title":"A re-evaluation of the role of host defence peptides in mammalian immunity","volume":"6","author":"Bowdish","year":"2005","journal-title":"Curr. Protein Pept. Sci."},{"key":"2025030707501490600_r11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cyto.2005.06.003","article-title":"Cytotoxic concentrations of alpha-defensins in the lungs of individuals with alpha 1-antitrypsin deficiency and moderate to severe lung disease","volume":"32","author":"Wencker","year":"2005","journal-title":"Cytokine"},{"key":"2025030707501490600_r12","doi-asserted-by":"crossref","first-page":"L514","DOI":"10.1152\/ajplung.00099.2003","article-title":"Role of human neutrophil peptides in lung inflammation associated with alpha1-antitrypsin deficiency","volume":"286","author":"Spencer","year":"2004","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"2025030707501490600_r13","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1007\/s000110050114","article-title":"Purification and characterization of defensins from cystic fibrosis sputum","volume":"46","author":"Soong","year":"1997","journal-title":"Inflamm. Res."},{"key":"2025030707501490600_r14","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1155\/2011\/139493","article-title":"Analysis of sputum markers in the evaluation of lung inflammation and functional impairment in symptomatic smokers and COPD patients","volume":"31","author":"Paone","year":"2011","journal-title":"Dis. Markers"},{"key":"2025030707501490600_r15","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1136\/thorax.57.7.623","article-title":"Raised plasma concentrations of alpha-defensins in patients with idiopathic pulmonary fibrosis","volume":"57","author":"Mukae","year":"2002","journal-title":"Thorax"},{"key":"2025030707501490600_r16","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1111\/j.1440-1843.2007.01061.x","article-title":"Elevated alpha-defensin levels in plasma of patients with pulmonary sarcoidosis","volume":"12","author":"Ashitani","year":"2007","journal-title":"Respirology"},{"key":"2025030707501490600_r17","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1164\/ajrccm.160.1.9807041","article-title":"Antibacterial components in bronchoalveolar lavage fluid from healthy individuals and sarcoidosis patients","volume":"160","author":"Agerberth","year":"1999","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2025030707501490600_r18","doi-asserted-by":"crossref","first-page":"L947","DOI":"10.1152\/ajplung.2001.280.5.L947","article-title":"Neutrophil defensins mediate acute inflammatory response and lung dysfunction in dose-related fashion","volume":"280","author":"Zhang","year":"2001","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"2025030707501490600_r19","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1164\/rccm.200907-1128OC","article-title":"Neutrophil alpha-defensins cause lung injury by disrupting the capillary-epithelial barrier","volume":"181","author":"Bdeir","year":"2010","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2025030707501490600_r20","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1016\/j.biochi.2010.02.023","article-title":"Structural determinants of host defense peptides for antimicrobial activity and target cell selectivity","volume":"92","author":"Takahashi","year":"2010","journal-title":"Biochimie"},{"key":"2025030707501490600_r21","doi-asserted-by":"crossref","first-page":"16275","DOI":"10.1074\/jbc.M110.102749","article-title":"Trp-26 imparts functional versatility to human alpha-defensin HNP1","volume":"285","author":"Wei","year":"2010","journal-title":"J. Biol. Chem."},{"key":"2025030707501490600_r22","doi-asserted-by":"crossref","first-page":"19653","DOI":"10.1074\/jbc.M611003200","article-title":"Toward understanding the cationicity of defensins: Arg and Lys versus their noncoded analogs","volume":"282","author":"Zou","year":"2007","journal-title":"J. Biol. Chem."},{"key":"2025030707501490600_r23","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/jlb.63.1.15","article-title":"Arginine-specific ADP-ribosyltransferases in leukocytes","volume":"63","author":"Saxty","year":"1998","journal-title":"J. Leukoc. Biol."},{"key":"2025030707501490600_r24","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1165\/ajrcmb.21.3.3638","article-title":"Selective expression of RT6 superfamily in human bronchial epithelial cells","volume":"21","author":"Balducci","year":"1999","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"2025030707501490600_r25","doi-asserted-by":"crossref","first-page":"8231","DOI":"10.1073\/pnas.122238899","article-title":"ADP ribosylation of human neutrophil peptide-1 regulates its biological properties","volume":"99","author":"Paone","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030707501490600_r26","doi-asserted-by":"crossref","first-page":"43039","DOI":"10.1074\/jbc.M510562200","article-title":"Why is the Arg5-Glu13 salt bridge conserved in mammalian alpha-defensins?","volume":"280","author":"Wu","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2025030707501490600_r27","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.ab.2009.06.028","article-title":"Precursor ion scanning and sequencing of arginine-ADP-ribosylated peptide by mass spectrometry","volume":"393","author":"Osago","year":"2009","journal-title":"Anal. Biochem."},{"key":"2025030707501490600_r28","doi-asserted-by":"crossref","first-page":"19796","DOI":"10.1073\/pnas.0910633106","article-title":"ADP-ribosylation of human defensin HNP-1 results in the replacement of the modified arginine with the noncoded amino acid ornithine","volume":"106","author":"Stevens","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030707501490600_r29","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1183\/09031936.03.00098803","article-title":"Innate immunity in the lung: how epithelial cells fight against respiratory pathogens","volume":"23","author":"Bals","year":"2004","journal-title":"Eur. Respir. J."},{"key":"2025030707501490600_r30","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1177\/1753465810396539","article-title":"The airway epithelium: more than just a structural barrier","volume":"5","author":"Tam","year":"2011","journal-title":"Ther. Adv. Respir. Dis."},{"key":"2025030707501490600_r31","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.jdermsci.2004.07.001","article-title":"Effect of defensin peptides on eukaryotic cells: primary epithelial cells, fibroblasts and squamous cell carcinoma cell lines","volume":"36","author":"Nishimura","year":"2004","journal-title":"J. Dermatol. Sci."},{"key":"2025030707501490600_r32","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1164\/ajrccm\/141.1.179","article-title":"Direct cytotoxicity of polymorphonuclear leukocyte granule proteins to human lung-derived cells and endothelial cells","volume":"141","author":"Okrent","year":"1990","journal-title":"Am. Rev. Respir. Dis."},{"key":"2025030707501490600_r33","doi-asserted-by":"crossref","first-page":"17054","DOI":"10.1074\/jbc.M603042200","article-title":"ADP-ribosyltransferase-specific modification of human neutrophil peptide-1","volume":"281","author":"Paone","year":"2006","journal-title":"J. Biol. Chem."},{"key":"2025030707501490600_r34","doi-asserted-by":"crossref","first-page":"5139","DOI":"10.1073\/pnas.84.15.5139","article-title":"Enhancement of choleragen ADP-ribosyltransferase activities by guanyl nucleotides and a 19-kDa membrane protein","volume":"84","author":"Tsai","year":"1987","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030707501490600_r35","doi-asserted-by":"crossref","first-page":"19591","DOI":"10.1074\/jbc.M210364200","article-title":"Regulatory role of arginine 204 in the catalytic activity of rat alloantigens ART2a and ART2b","volume":"278","author":"Stevens","year":"2003","journal-title":"J. Biol. Chem."},{"issue":"1","key":"2025030707501490600_r36","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/S0003-2697(03)00289-6","article-title":"On the analysis of protein self-association by sedimentation velocity analytical ultracentrification","volume":"301","author":"Schuck","year":"2003","journal-title":"Anal Biochem."},{"key":"2025030707501490600_r37","doi-asserted-by":"crossref","first-page":"17","DOI":"10.3109\/01902149109063278","article-title":"Interleukin-8 (IL-8): the major neutrophil chemotactic factor in the lung","volume":"17","author":"Kunkel","year":"1991","journal-title":"Exp. Lung Res."},{"key":"2025030707501490600_r38","first-page":"223","article-title":"Increased expression of proinflammatory chemokines in bronchoalveolar lavage cells of patients with progressing idiopathic pulmonary fibrosis and sarcoidosis","volume":"46","author":"Ziegenhagen","year":"1998","journal-title":"J. Investig. Med."},{"key":"2025030707501490600_r39","doi-asserted-by":"crossref","first-page":"2936","DOI":"10.1182\/blood-2005-06-2314","article-title":"Human neutrophil peptides induce interleukin-8 production through the P2Y6 signaling pathway","volume":"107","author":"Khine","year":"2006","journal-title":"Blood"},{"key":"2025030707501490600_r40","doi-asserted-by":"crossref","first-page":"L508","DOI":"10.1152\/ajplung.00076.2004","article-title":"Differential effects of alpha- and beta-defensin on cytokine production by cultured human bronchial epithelial cells","volume":"288","author":"Sakamoto","year":"2005","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"2025030707501490600_r41","doi-asserted-by":"crossref","first-page":"8944","DOI":"10.1074\/jbc.M111.332205","article-title":"Sometimes it takes two to tango: contributions of dimerization to functions of human \u03b1-defensin HNP1 peptide","volume":"287","author":"Pazgier","year":"2012","journal-title":"J. Biol. Chem."},{"issue":"Suppl. A","key":"2025030707501490600_r42","doi-asserted-by":"crossref","first-page":"S35","DOI":"10.1016\/S1526-0542(04)90008-5","article-title":"Epithelial cells and fibroblasts: structural repair and remodelling in the airways","volume":"5","author":"Sacco","year":"2004","journal-title":"Paediatr. Respir. Rev."},{"key":"2025030707501490600_r43","doi-asserted-by":"crossref","first-page":"1839","DOI":"10.1016\/j.lfs.2007.02.014","article-title":"Alpha-defensin enhances expression of HSP47 and collagen-1 in human lung fibroblasts","volume":"80","author":"Yoshioka","year":"2007","journal-title":"Life Sci."},{"key":"2025030707501490600_r44","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1016\/j.lfs.2006.11.016","article-title":"The concentration-dependent chemokine release and pro-apoptotic effects of neutrophil-derived alpha-defensin-1 on human bronchial and alveolar epithelial cells","volume":"80","author":"Liu","year":"2007","journal-title":"Life Sci."},{"key":"2025030707501490600_r45","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1189\/jlb.72.1.167","article-title":"Human neutrophil defensins induce lung epithelial cell proliferation in vitro","volume":"72","author":"Aarbiou","year":"2002","journal-title":"J. Leukoc. Biol."},{"key":"2025030707501490600_r46","doi-asserted-by":"crossref","first-page":"5240","DOI":"10.1021\/jm100378b","article-title":"Oncocin (VDKPPYLPRPRPPRRIYNR-NH2): a novel antibacterial peptide optimized against Gram-negative human pathogens","volume":"53","author":"Knappe","year":"2010","journal-title":"J. Med. Chem."},{"key":"2025030707501490600_r47","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/nrmicro1098","article-title":"Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria?","volume":"3","author":"Brogden","year":"2005","journal-title":"Nat. Rev. Microbiol."},{"key":"2025030707501490600_r48","doi-asserted-by":"crossref","first-page":"5035","DOI":"10.1128\/IAI.00695-09","article-title":"Electropositive charge in alpha-defensin bactericidal activity: functional effects of Lys-for-Arg substitutions vary with the peptide primary structure","volume":"77","author":"Llenado","year":"2009","journal-title":"Infect. Immun."},{"key":"2025030707501490600_r49","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1002\/psc.316","article-title":"Tryptic hydrolysis of hGH-RH(1-29)-NH2 analogues containing Lys or Orn in positions 12 and 21","volume":"7","author":"Witkowska","year":"2001","journal-title":"J. Pept. Sci."},{"key":"2025030707501490600_r50","doi-asserted-by":"crossref","first-page":"3446","DOI":"10.1128\/iai.60.8.3446-3447.1992","article-title":"Mouse neutrophils lack defensins","volume":"60","author":"Eisenhauer","year":"1992","journal-title":"Infect. Immun."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/193\/12\/6144\/62227490\/1303068.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/193\/12\/6144\/62227490\/1303068.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T08:21:57Z","timestamp":1741335717000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/193\/12\/6144\/7960281"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,12]]},"references-count":50,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2014,12,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1303068","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2014,12]]},"published":{"date-parts":[[2014,12]]}}}