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Neutrophil Peptide-1 Alters the Biological Activities of Human ADP

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Neutrophil Peptide-1 Alters the Biological Activities of Human ADP Nonenzymatic Conversion of ADP-Ribosylated Arginines to Ornithine Alters the Biological Activities of Human Neutrophil Peptide-1 This information is current as of September 27, 2021. Linda A. Stevens, Joseph T. Barbieri, Grzegorz Piszczek, Amy N. Otuonye, Rodney L. Levine, Gang Zheng and Joel Moss J Immunol published online 12 November 2014 http://www.jimmunol.org/content/early/2014/11/11/jimmun Downloaded from ol.1303068 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 *average by guest on September 27, 2021 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 © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published November 12, 2014, doi:10.4049/jimmunol.1303068 The Journal of Immunology Nonenzymatic Conversion of ADP-Ribosylated Arginines to Ornithine Alters the Biological Activities of Human Neutrophil Peptide-1 Linda A. Stevens,* Joseph T. Barbieri,† Grzegorz Piszczek,‡ Amy N. Otuonye,* Rodney L. Levine,x Gang Zheng,{ and Joel Moss* Activated neutrophils, recruited to the airway of diseased lung, release human neutrophil peptides (HNP1–4) 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 Downloaded from 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-b1 release from A549 cells, and to serve as ART1 substrates. HNP and the three analogs had similar effects on IL-8 and TGF-b1 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, http://www.jimmunol.org/ 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. The Journal of Immunology, 2014, 193: 000–000. olymorphonuclear leukocytes migrate into the lung to the disease (7–9). In the bronchoalveolar lavage fluid (BALF) of healthy site of infection, inflammation, or other disease processes volunteers, concentrations of HNP1–3 are 0.2 mg/ml, but may in- in response to complex signaling events. After activation, P crease 6-fold during infection and 50-fold in inflammatory lung by guest on September 27, 2021 neutrophils release antimicrobial a-defensins (human neutrophil diseases (10). Elevated levels of defensins were found in the BALF peptides [HNP]1–4), cationic, amphipathic, arginine-rich peptides of patients with a1-antitrypsin deficiency (11, 12), in the sputum of with diverse biological activities (1). In addition to killing micro- patients with cystic fibrosis (13) and chronic obstructive pulmonary organisms, defensins promote proliferation (2, 3) and stimulate disease (14), and in the serum of patients with interstitial lung dis- the release of neutrophil chemotactic factor, IL-8, and TGF-b1 ease [e.g., idiopathic pulmonary fibrosis (15), sarcoidosis (16, 17)]. from lung epithelial cells and fibroblasts (4, 5). The in vitro effects Defensins at low concentrations increased proliferation and collagen on proliferation of airway epithelial cells suggested a role for synthesis in lung fibroblasts, possibly participating in the formation of defensins in wound repair. Indeed, wound closure and mucin gene the fibroproliferative lesions seen in inflammatory pulmonary diseases expression were enhanced by HNP1–3 in vitro (6). (3). Intratracheal instillation of defensins (HNP1–3) into the lungs of It has been proposed that defensins released at the site of in- mice that do not express neutrophil-derived HNP caused acute lung flammation or infections are also involved in the pathogenesis of inflammation and dysfunction (18). Transgenic mice that expressed a-defensins (HNP1, 2) in their neutrophils had more severe, acid- *Cardiovascular and Pulmonary Branch, National, Heart, Lung, and Blood Institute, induced acute lung injury than did their wild-type counterparts (19). National Institutes of Health, Bethesda, MD 20892; †Microbiology and Molecular ‡ Net charge, amphipathicity, hydrophobicity, and tertiary structure Genetics, Medical College of Wisconsin, Milwaukee, WI 53226; Biophysics Core Facility, National, Heart, Lung, and Blood Institute, National Institutes of Health, are critical for the antimicrobial activity of defensins (20). In addi- x Bethesda, MD 20892; Laboratory of Biochemistry, National, Heart, Lung, and tion to the hydrophobicity of tryptophan 26 (21), the positive charge Blood Institute, National Institutes of Health, Bethesda, MD 20892; and {Office of Biostatistics Research, National, Heart, Lung, and Blood Institute, National Institutes of three arginine residues (22) is essential for the antimicrobial activ- of Health, Bethesda, MD 20892 ity of HNP-1. ART1, an arginine-specific ADP ribosyltransferase Received for publication November 14, 2013. Accepted for publication October 1, (ART) expressed on the surface of airway epithelial cells and neu- 2014. trophils (23, 24), catalyzes the transfer of the ADP-ribose moiety of This work was supported by the Intramural Research Program of the National In- NAD to arginine 14 of HNP-1, inhibiting its antibacterial and cy- stitutes of Health, National Heart, Lung, and Blood Institute. totoxic activities (25). The primary sequence of HNP1–3 contains Address correspondence and reprint requests to Dr. Joel Moss, Room 6D05, Building 10, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892-1590. arginines at positions 5, 14, 15, and 24. Arginine 5 forms a salt E-mail address: [email protected] bridge with glutamic acid 13 that is required for folding stability Abbreviations used in this article: ART, ADP ribosyltransferase; BALF, bronchoal- (26). Arginines 14 and 24 in HNP-1 are ADP ribosylated by ART1, veolar lavage fluid; HNP, human neutrophil peptide; mART, mouse ART; NHLF, and ADP-ribosylated arginines can be converted nonenzymatically to normal human lung fibroblast; SAEC, small airway epithelial cell. ornithine by nucleophilic attack of water on the guanidino carbon Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 with probable release of ADP-ribose-carbamate (27, 28). Mono- and www.jimmunol.org/cgi/doi/10.4049/jimmunol.1303068 2 ACTIVITY OF HNP-1–CONTAINING ORNITHINE di-ADP–ribosylated HNP-1 and ADP-ribosylated HNP-(ornithine) RPMI 1640, respectively, with 10% FBS. Normal human lung fibroblasts were isolated from the BALF of a patient with idiopathic pulmonary (NHLF) and normal human small airway epithelial cells (SAEC) were fibrosis, suggesting that posttranslationally modified HNP-1 is found purchased from Clonetics (Walkersville, MD) and grown, respectively, in fibroblast media or small airway epithelial cell complete medium supplied in the diseased airway. The relative ratios of native HNP and by the company. All cells were grown at 37˚C in 5% CO2. derivatives vary among patients. Airway epithelial cells play a critical role in host defense by se- Preparation of mouse ADP-ribosyltransferase-1 creting molecules (e.g., cytokines, chemokines, antimicrobial peptides) Rat mammary adenocarcinoma cells (NMU) transfected with plasmids that attract neutrophils and kill microorganisms (29, 30). IL-8, released containing the mouse ART (mART)1 gene were grown in Eagle’s MEM from epithelial cells in response to HNP-1, amplifies the inflammatory with 10% FBS and 0.5 mg/ml Geneticin (G418). Proteins released from the cells by incubation with phosphatidylinositol-specific phospholipase C, response by recruiting neutrophils that can, in turn, release additional which cleaves the GPI anchor, were collected in PBS (33), and ADP- HNP. Defensins at concentrations found in disease may be toxic to ribosyltransferase activity was assayed, as described (34). lung epithelial cells, endothelial cells, and normal lung fibroblasts,
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