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Role of Nicotinamide Adenine Dinucleotide Phosphate Oxidase 1 in Oxidative Burst Response to Toll-Like Receptor 5 Signaling in Large Intestinal Epithelial Cells This information is current as of September 27, 2021. Tsukasa Kawahara, Yuki Kuwano, Shigetada Teshima-Kondo, Ryu Takeya, Hideki Sumimoto, Kyoichi Kishi, Shohko Tsunawaki, Toshiya Hirayama and Kazuhito Rokutan J Immunol 2004; 172:3051-3058; ; Downloaded from doi: 10.4049/jimmunol.172.5.3051 http://www.jimmunol.org/content/172/5/3051 http://www.jimmunol.org/ References This article cites 32 articles, 18 of which you can access for free at: http://www.jimmunol.org/content/172/5/3051.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 27, 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 © 2004 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Role of Nicotinamide Adenine Dinucleotide Phosphate Oxidase 1 in Oxidative Burst Response to Toll-Like Receptor 5 Signaling in Large Intestinal Epithelial Cells1 Tsukasa Kawahara,* Yuki Kuwano,* Shigetada Teshima-Kondo,* Ryu Takeya,† Hideki Sumimoto,† Kyoichi Kishi,* Shohko Tsunawaki,‡ Toshiya Hirayama,§ and Kazuhito Rokutan2* The NADPH oxidase 1 (Nox1) is a gp91phox homologue preferentially expressed in the colon. We have established primary cultures of guinea pig large intestinal epithelial cells giving 90% purity of surface mucous cells. These cells spontaneously released su- ؊ phox phox phox peroxide anion (O2 ) of 160 nmol/mg protein/h and expressed the Nox1, p22 , p67 , and Rac1 mRNAs, but not the gp91 , Nox4, p47phox, p40phox, and Rac2 mRNAs. They also expressed novel homologues of p47phox and p67phox (p41nox and p51nox, Downloaded from respectively). Human colon cancer cell lines (T84 and Caco2 cells) expressed the Nox1, p22phox, p51nox, and Rac1 mRNAs, but not ؊ nox the other NADPH component mRNAs, and secreted only small amounts of O2 (<2 nmol/mg protein/h). Cotransfection of p41 nox ؊ and p51 cDNAs in T84 cells enhanced PMA-stimulated O2 release 5-fold. Treatment of the transfected T84 cells with recom- ؊ binant flagellin (rFliC) from Salmonella enteritidis further augmented the O2 release in association with the induction of Nox1 ؊ nox nox protein. The enhanced O2 production by cotransfection of p41 and p51 vectors further augmented the rFliC-stimulated IL-8 release from T84 cells. T84 cells expressed the Toll-like receptor 5, and rFliC rapidly phosphorylated TGF-␤-activated kinase http://www.jimmunol.org/ 1 and TGF-␤-activated kinase 1-binding protein 1. A potent inhibitor for NF-␬B (pyrrolidine dithiocarbamate) significantly ؊ nox nox blocked the rFliC-primed increase in O2 production and induction of Nox1 protein. These results suggest that p41 and p51 are involved in the Nox1 activation in surface mucous cells of the colon, and besides that, epithelial cells discern pathogenicities among bacteria to appropriately operate Nox1 for the host defense. The Journal of Immunology, 2004, 172: 3051–3058. eactive oxygen species (ROS),3 notably superoxide anion Recently, two families of gp91phox homologues have been identi- Ϫ (O2 ) and hydrogen peroxide, operate on a variety of fied: NADPH oxidase (Nox) and dual oxidase (Duox) families (5). physiological processes, including host defense, gene ex- The Nox family comprises Nox1 (initially termed Mox1 or NOH- by guest on September 27, 2021 R phox pression, oxygen sensing, regulation of vascular tone, bone resorp- 1), Nox2 (renamed gp91 ), Nox3, Nox4 (Renox), and Nox5 tion, apoptosis, cell growth, and transformation (for reviews, see (6–10). These homologues conserve binding sites for heme, FAD, Ϫ Refs. 1–3). The best-known O2 -producing enzyme is the phago- and NADPH of Nox2 (5), and are preferentially expressed in cyte respiratory burst oxidase that plays a crucial role in a process nonphagocytic cells. The Duox family members are Duox1 and of killing microorganisms. The catalytic core of this oxidase is the Duox2 (initially termed ThOX1 and ThOX2, respectively), which phox membrane-integrated flavocytochrome b558 composed of p22 have a peroxidase homology domain plus two EF-hand motifs, as and gp91phox subunits, the latter having binding sites for heme, well as binding sites for heme, FAD, and NADPH (5). Of these flavin adenine dinucleotide (FAD), and NADPH, and transfers an family members, the Nox1 mRNA is predominantly expressed in Ϫ electron from NADPH to molecular oxygen to generate O2 (4). human colon tissue and a carcinoma cell line, Caco2 cells (6, 7). However, physiological roles of Nox1 in large intestinal epithelial *Department of Nutrition, School of Medicine, University of Tokushima, Tokushima, cells (LIEC) are not fully understood. Japan; †Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; ‡De- We previously reported that primary cultures of guinea pig gas- partment of Infectious Diseases, National Research Institute for Child Health and Ϫ Development, Tokyo, Japan; and §Department of Bacteriology, Institute of Tropical tric pit cells expressed Nox1 and spontaneously secreted O2 (11, Medicine, Nagasaki University, Nagasaki, Japan 12). ROS derived from Nox1 in the pit cells were essential for their Received for publication June 12, 2003. Accepted for publication December 22, 2003. growth at least in vitro (12). Furthermore, Helicobacter pylori LPS The costs of publication of this article were defrayed in part by the payment of page stimulated the Toll-like receptor (TLR) 4 signaling and activated charges. This article must therefore be hereby marked advertisement in accordance Ϫ Nox1 (13, 14). The increased O2 production and enhanced acti- with 18 U.S.C. Section 1734 solely to indicate this fact. vation of NF-␬B resulted in the induction of the TNF-␣ and cy- 1 This study was supported by a grant-in-aid for scientific research from Japan Society clooxygenase II mRNAs in pit cells themselves (12), suggesting a for the Promotion of Science (14370184), and Japan Society for the Promotion of Science Research Fellowships for Young Scientists (04127). potential role of Nox1 in inflammatory and immune responses 2 Address correspondence and reprint requests to Dr. Kazuhito Rokutan, Department against H. pylori. phox of Nutrition, School of Medicine, University of Tokushima, 3-18-15 Kuramoto-cho, The flavocytochrome b558 requires cytosolic proteins, p67 , Tokushima 770-8503, Japan. E-mail address: [email protected] p47phox, and a small GTPase Rac for electron-transfer reactions to 3 Abbreviations used in this paper: ROS, reactive oxygen species; DF, DMEM-Ham’s form O Ϫ (4). P40phox associates with p67phox and enhances mem- F-12; Duox, dual oxidase; FAD, flavin adenine dinucleotide; LIEC, large intestinal 2 Ϫ phox phox epithelial cell; NBT, nitroblue tetrazolium; Nox, NADPH oxidase; O2 , superoxide brane translocation of p67 and p47 in stimulated phago- anion; PAS, periodic acid-Schiff; PDTC, pyrrolidine dithiocarbamate; PVDF, poly- cytes (15). However, it remains to be elucidated whether these vinylidene difluoride filter; rFliC, recombinant structural protein of flagella filament; SOD, superoxide dismutase; TAB1, TAK1-binding protein 1; TAK1, TGF-␤-acti- cytosolic factors are necessary for activation of the other Nox and vated kinase 1; TLR, Toll-like receptor. Duox family members. Copyright © 2004 by The American Association of Immunologists, Inc. 0022-1767/04/$02.00 3052 Nox1 IN LIEC In this study, we have established primary cultures of guinea pig dues 1–15), and recombinant human p67phox were provided, as previously LIEC with 90% purity of surface mucous cells and have found that described (13). Membrane, cytosolic, and whole cell fractions were pre- these cells also produce O Ϫ even at a higher rate than that of pared from cultured cells, as previously described (11). Each sample of 20 2 ␮g protein per lane was separated by SDS-PAGE using an 8% polyacryl- gastric pit cells. Guinea pig LIEC expressed novel genes encoding amide gel and transferred to a polyvinylidene difluoride filter (PVDF). nox phox nox phox p41 (a p47 homologue) and p51 (a p67 homologue), After blocking nonspecific binding sites with 4% purified milk casein, the which have recently cloned in mouse and human, being named as PVDF was incubated for1hatroom temperature with one of the above the NOX organizer 1 and NOX activator 1 (16–18), respectively. primary Abs at a 1/1000 dilution. After being washed with PBS containing 0.05% Tween 20, bound Abs were detected by an ECL Western blotting Cotransfection of these two homologues was shown to up-regulate Ϫ detection system (Amersham Pharmacia Biotech). Bound Abs were then O2 -producing capability of Nox1, and in situ hybridization dem- removed, and the PVDF was reblotted with a mAb against ␤-actin (On- onstrated that the p41nox and p51nox transcripts were expressed in cogene Research
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  • The Human Cathelicidin LL-37 — a Pore-Forming Antibacterial Peptide and Host-Cell Modulator☆

    The Human Cathelicidin LL-37 — a Pore-Forming Antibacterial Peptide and Host-Cell Modulator☆

    Biochimica et Biophysica Acta 1858 (2016) 546–566 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbamem The human cathelicidin LL-37 — A pore-forming antibacterial peptide and host-cell modulator☆ Daniela Xhindoli, Sabrina Pacor, Monica Benincasa, Marco Scocchi, Renato Gennaro, Alessandro Tossi ⁎ Department of Life Sciences, University of Trieste, via Giorgeri 5, 34127 Trieste, Italy article info abstract Article history: The human cathelicidin hCAP18/LL-37 has become a paradigm for the pleiotropic roles of peptides in host de- Received 7 August 2015 fence. It has a remarkably wide functional repertoire that includes direct antimicrobial activities against various Received in revised form 30 October 2015 types of microorganisms, the role of ‘alarmin’ that helps to orchestrate the immune response to infection, the Accepted 5 November 2015 capacity to locally modulate inflammation both enhancing it to aid in combating infection and limiting it to pre- Available online 10 November 2015 vent damage to infected tissues, the promotion of angiogenesis and wound healing, and possibly also the elimi- Keywords: nation of abnormal cells. LL-37 manages to carry out all its reported activities with a small and simple, Cathelicidin amphipathic, helical structure. In this review we consider how different aspects of its primary and secondary LL-37 structures, as well as its marked tendency to form oligomers under physiological solution conditions and then hCAP-18 bind to molecular surfaces as such, explain some of its cytotoxic and immunomodulatory effects. We consider CRAMP its modes of interaction with bacterial membranes and capacity to act as a pore-forming toxin directed by our Host defence peptide organism against bacterial cells, contrasting this with the mode of action of related peptides from other species.