白血球所產生的氧活性分子在身體對抗外來病菌的入侵，以及發炎反應的免疫調控上是很重要的。NADPH 氧化酶是人體內一個產生氧活性分子的重要酵素。白血球的NADPH oxidase是一個由多個單元體所組成的複合酵素，主要包含由gp91phox與p22phox所構成之細胞膜嵌合的異質二聚體，以及位在細胞質內的組成單元,其中包括有p40phox、p47phox、p67phox以及小G蛋白質（small GTPase）Rac。針對不同的環境調整NADPH 氧化酶的活性是免疫細胞控制其活化狀態的重要機制。 若人類白血球的NADPH oxidase發生變異，會導致白血球的呼吸爆發能力喪失，因而導致慢性肉芽腫病（chronic granulomatous disease，CGD）。其中因X染色體上編碼成gp91phox蛋白質的CYBB基因發生突變所導致的慢性肉芽腫病是最常見的一型。在本研究中, 我們試著藉由thapsigargin以及嘌呤二核苷酸(flavin adenine dinucleotide，FAD）的處理，來治療從一個gp91phox帶有H338Y突變的慢性肉芽腫病病人身上所取出來的白血球其氧活性分子的製造能力。研究結果顯示，此藥物處理會影響具鈣離子依存性之陪伴蛋白的功能，因而使得帶有H338Y突變的gp9aphox蛋白質可以由內質網釋出，並進行後續的蛋白質修飾成熟作用。因而可以回復部分的氧活性分子製造能力，並可增進其體外測試的殺菌能力，以及對於帶慢性肉芽腫病的老鼠具有保護作用，可減少其因腹部注射葡萄球菌實驗所導致的腹部膿瘍的產生。這些結果顯示，特殊CGD病人的白血球經由體外thapsigargin-FAD的處理，可以有效地恢復其製造氧活性分子的能力。不同於基因突變導致NADPH oxidase活性缺失的情形，正常NADPH oxidase的活性可以因為暴露在包括LPS或一些細胞激素等“priming”物質的情形而增加，其可能機制是藉由增加氧化酶之蛋白質組成物的含量、蛋白質組成物的胞內移動或是其磷酸化修飾等機制而達成。在本論文中,我們是利用IL-19來刺激白血球，以研究priming的作用機制。IL-19是一個和氣喘、乾癬，以及敗血症等發炎性疾病具高度相關的細胞激素。我們發現IL-19對於人類白血球以及經由DMSO所促成分化的HL60細胞具有priming的能力，其可以藉由促進p47phox蛋白質的胞內位移，以及絲胺酸的磷酸化作用而使得氧活性分子的製造能力增加。STAT3和p38MAPK等這些訊息傳遞分子也包含在IL-19以及LPS所導致的訊息傳遞路徑中。更進一步在IL-19的抗體中和實驗中，我們發現IL-19在LPS所導致的發炎反應中扮演相當重要的角色。總結來說，經由本研究，我們增進了對白血球NADPH oxidase的分子作用機制的瞭解，這可以幫助我們去調控由氧活性分子所導致的組織發炎反應，並且在未來對於處理因NADPH oxidase功能異常所導致的相關疾病會有重要的幫助。

The production of reactive oxygen species (ROS) by phagocytic leukocytes plays an important role in host defense and regulation of inflammatory processes. NADPH oxidase is one of the most important ROS-producing enzymes in the human body. Leukocyte NADPH oxidase is a multiple-component enzyme composed of both membrane-bound gp91phox-p22phox heterodimer and cytoplasmic components, which include p40phox, p47phox, p67phox, and small GTPase Rac. Regulation of the enzyme activity of leukocyte NADPH oxidase in different tissue milieu is important for the activation of immune cells. Loss-of-function mutations in leukocyte NADPH oxidase genes lead to defective respiratory burst in leukocytes and cause chronic granulomatous diseases (CGD) in humans. The most common form of CGD is caused by mutations in gp91phox which is encoded by the CYBB gene on the X-chromosome. The dissertation is organized as followed. In the first part of this study, we devised a method to rescue the ROS-producing capacity of the leukocytes from a CGD patient with H338Y mutant in gp91phox by treating with thapsigargin and flavin adenine dinucleotide (FAD). This treatment interfered with the function of calcium-dependent chaperone leading to release the H338Y mutant gp91phox protein from ER to be further processed and hence partially restored the protein quantity and quality. This cellular treatment restored the ROS production activity, enhanced the bactericidal activity in vitro and protected animals from staphylococcus-induced peritoneal abscess formation in a mouse model of CGD. These results indicate that thapsigargin-FAD ex vivo treatment is effective in rescuing the ROS-producing activity of leukocytes in selected CGD patients. In physiological conditions, the oxidase activity can be increased by prior exposure to "priming" agents, such as LPS or cytokines, through enhancing the quantity of the oxidase subunits, intracellular protein translocation or protein phosphorylation. In the second part of this study, we clarified the molecular mechanisms of the IL-19-mediated priming effect, which was implicated in inflammation in asthmatic, psoriatic, and septic patients. We found that IL-19 may prime the NADPH oxidase of human leukocyte and DMSO-differentiated HL-60 cells and thus lead to stronger subsequent respiratory bursts by inducing the translocation and serine phosphorylation of p47phox. STAT3 and p38PMAK were involved in IL-19- and LPS-induced signaling pathway. We further verified the role of IL-19 in regulating the inflammatory effect of LPS by treating the cells with anti-IL-19 neutralizing Abs. In conclusion, our results on the molecular mechanisms regulating the leukocyte NADPH oxidase including restoring mutant NADPH oxidase function with cellular treatment and priming in normal oxidase will be the basis for further scientific pursuit and clinical application in the near future.

Ahlin,A., Larfars,G., Elinder,G., Palmblad,J., and Gyllenhammar,H. (1999). Gamma interferon treatment of patients with chronic granulomatous disease is associated with augmented production of nitric oxide by polymorphonuclear neutrophils. Clin. Diagn. Lab Immunol. 6, 420-424.
Ambruso,D.R., Knall,C., Abell,A.N., Panepinto,J., Kurkchubasche,A., Thurman,G., Gonzalez-Aller,C., Hiester,A., deBoer,M., Harbeck,R.J., Oyer,R., Johnson,G.L., and Roos,D. (2000). Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation. Proc. Natl. Acad. Sci. U. S. A. 97, 4654-4659.
Arruda,M.A. and Barja-Fidalgo,C. (2009). NADPH oxidase activity: In the crossroad of neutrophil life and death. Front Biosci. 14, 4546-4556.
Babior,B.M. (2004). NADPH oxidase. Curr. Opin. Immunol. 16, 42-47.
Banfi,B., Clark,R.A., Steger,K., and Krause,K.H. (2003). Two novel proteins activate superoxide generation by the NADPH oxidase NOX1. J. Biol. Chem. 278, 3510-3513.
Banfi,B., Molnar,G., Maturana,A., Steger,K., Hegedus,B., Demaurex,N., and Krause,K.H. (2001). A Ca(2+)-activated NADPH oxidase in testis, spleen, and lymph nodes. J. Biol. Chem. 276, 37594-37601.
Bedard,K. and Krause,K.H. (2007). The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev. 87, 245-313.
Bross,P., Corydon,T.J., Andresen,B.S., Jorgensen,M.M., Bolund,L., and Gregersen,N. (1999). Protein misfolding and degradation in genetic diseases. Hum. Mutat. 14, 186-198.
Burritt,J.B., DeLeo,F.R., McDonald,C.L., Prigge,J.R., Dinauer,M.C., Nakamura,M., Nauseef,W.M., and Jesaitis,A.J. (2001). Phage display epitope mapping of human neutrophil flavocytochrome b558. Identification of two juxtaposed extracellular domains. J. Biol. Chem. 276, 2053-2061.
Bylund,J., Karlsson,A., Boulay,F., and Dahlgren,C. (2002). Lipopolysaccharide-induced granule mobilization and priming of the neutrophil response to Helicobacter pylori peptide Hp(2-20), which activates formyl peptide receptor-like 1. Infect. Immun. 70, 2908-2914.
Caldefie-Chezet,F., Walrand,S., Moinard,C., Tridon,A., Chassagne,J., and Vasson,M.P. (2002). Is the neutrophil reactive oxygen species production measured by luminol and lucigenin chemiluminescence intra or extracellular? Comparison with DCFH-DA flow cytometry and cytochrome c reduction. Clin. Chim. Acta. 319, 9-17.
Carvou,N., Norden,A.G., Unwin,R.J., and Cockcroft,S. (2007). Signalling through phospholipase C interferes with clathrin-mediated endocytosis. Cell Signal. 19, 42-51.
Cheng,G. and Lambeth,J.D. (2004). NOXO1, regulation of lipid binding, localization, and activation of Nox1 by the Phox homology (PX) domain. J. Biol. Chem. 279, 4737-4742.
Chuang,K.P., Huang,Y.F., Hsu,Y.L., Liu,H.S., Chen,H.C., and Shieh,C.C. (2004). Ligation of lymphocyte function-associated antigen-1 on monocytes decreases very late antigen-4-mediated adhesion through a reactive oxygen species dependent pathway. Blood 104, 4046-4053.
Chuang,K.P., Tsai,W.S., Wang,Y.J., and Shieh,C.C. (2003). Superoxide Activates Very Late Antigen-4 on an Eosinophil Cell Line and Increases Cellular Binding to Vascular Cell Adhesion Molecule-1. Eur. J. Immunol. 33, 645-655.
Dahlgren,C., Karlsson,A., and Bylund,J. (2007). Measurement of respiratory burst products generated by professional phagocytes. Methods Mol. Biol. 412, 349-363.
Dale,D.C., Boxer,L., and Liles,W.C. (2008). The phagocytes: neutrophils and monocytes. Blood. 112, 935-945.
Dang,P.M., Stensballe,A., Boussetta,T., Raad,H., Dewas,C., Kroviarski,Y., Hayem,G., Jensen,O.N., Gougerot-Pocidalo,M.A., and El-Benna,J. (2006). A specific p47phox -serine phosphorylated by convergent MAPKs mediates neutrophil NADPH oxidase priming at inflammatory sites. J. Clin. Invest. 116, 2033-2043.
De Ravin,S.S., Naumann,N., Cowen,E.W., Friend,J., Hilligoss,D., Marquesen,M., Balow,J.E., Barron,K.S., Turner,M.L., Gallin,J.I., and Malech,H.L. (2008). Chronic granulomatous disease as a risk factor for autoimmune disease. J. Allergy Clin. Immunol. 122, 1097-1103.
DeLeo,F.R., Burritt,J.B., Yu,L., Jesaitis,A.J., Dinauer,M.C., and Nauseef,W.M. (2000). Processing and maturation of flavocytochrome b558 include incorporation of heme as a prerequisite for heterodimer assembly. J. Biol. Chem. 275, 13986-13993.
DeLeo,F.R., Renee,J., McCormick,S., Nakamura,M., Apicella,M., Weiss,J.P., and Nauseef,W.M. (1998). Neutrophils exposed to bacterial lipopolysaccharide upregulate NADPH oxidase assembly. J. Clin. Invest. 101, 455-463.
Delisle,B.P., Anderson,C.L., Balijepalli,R.C., Anson,B.D., Kamp,T.J., and January,C.T. (2003). Thapsigargin selectively rescues the trafficking defective LQT2 channels G601S and F805C. J. Biol. Chem. 278, 35749-35754.
Dewas,C., Dang,P.M., Gougerot-Pocidalo,M.A., and El-Benna,J. (2003). TNF-alpha induces phosphorylation of p47(phox) in human neutrophils: partial phosphorylation of p47phox is a common event of priming of human neutrophils by TNF-alpha and granulocyte-macrophage colony-stimulating factor. J. Immunol. 171, 4392-4398.
Dewas,C., Fay,M., Gougerot-Pocidalo,M.A., and El-Benna,J. (2000). The mitogen-activated protein kinase extracellular signal-regulated kinase 1/2 pathway is involved in formyl-methionyl-leucyl-phenylalanine-induced p47phox phosphorylation in human neutrophils. J. Immunol. 165, 5238-5244.
Dinauer,M.C., Curnutte,J.T., Rosen,H., and Orkin,S.H. (1989). A missense mutation in the neutrophil cytochrome b heavy chain in cytochrome-positive X-linked chronic granulomatous disease. J. Clin. Invest. 84, 2012-2016.
Dumoutier,L., Leemans,C., Lejeune,D., Kotenko,S.V., and Renauld,J.C. (2001). Cutting edge: STAT activation by IL-19, IL-20 and mda-7 through IL-20 receptor complexes of two types. J. Immunol. 167, 3545-3549.
Dunican,A., Grutkoski,P., Leuenroth,S., Ayala,A., and Simms,H.H. (2000). Neutrophils regulate their own apoptosis via preservation of CXC receptors. J. Surg. Res. 90, 32-38.
Egan,M.E., Glockner-Pagel,J., Ambrose,C., Cahill,P.A., Pappoe,L., Balamuth,N., Cho,E., Canny,S., Wagner,C.A., Geibel,J., and Caplan,M.J. (2002). Calcium-pump inhibitors induce functional surface expression of Delta F508-CFTR protein in cystic fibrosis epithelial cells. Nat. Med. 8, 485-492.
Egan,M.E., Pearson,M., Weiner,S.A., Rajendran,V., Rubin,D., Glockner-Pagel,J., Canny,S., Du,K., Lukacs,G.L., and Caplan,M.J. (2004). Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects. Science. 304, 600-602.
El Benna J., Faust,R.P., Johnson,J.L., and Babior,B.M. (1996). Phosphorylation of the respiratory burst oxidase subunit p47phox as determined by two-dimensional phosphopeptide mapping. Phosphorylation by protein kinase C, protein kinase A, and a mitogen-activated protein kinase. J. Biol. Chem. 271, 6374-6378.
El Benna J., Hayem,G., Dang,P.M., Fay,M., Chollet-Martin,S., Elbim,C., Meyer,O., and Gougerot-Pocidalo,M.A. (2002). NADPH oxidase priming and p47phox phosphorylation in neutrophils from synovial fluid of patients with rheumatoid arthritis and spondylarthropathy. Inflammation. 26, 273-278.
El Benna,J., Dang,P.M., and Gougerot-Pocidalo,M.A. (2008). Priming of the neutrophil NADPH oxidase activation: role of p47phox phosphorylation and NOX2 mobilization to the plasma membrane. Semin. Immunopathol. 30, 279-289.
El Benna,J., Dang,P.M., Gougerot-Pocidalo,M.A., Marie,J.C., and Braut-Boucher,F. (2009). p47phox, the phagocyte NADPH oxidase/NOX2 organizer: structure, phosphorylation and implication in diseases. Exp. Mol. Med. 41, 217-225.
Elbim,C., Guichard,C., Dang,P.M., Fay,M., Pedruzzi,E., Demur,H., Pouzet,C., El,B.J., and Gougerot-Pocidalo,M.A. (2005). Interleukin-18 primes the oxidative burst of neutrophils in response to formyl-peptides: role of cytochrome b558 translocation and N-formyl peptide receptor endocytosis. Clin. Diagn. Lab Immunol. 12, 436-446.
Faust,L.R., el,B.J., Babior,B.M., and Chanock,S.J. (1995). The phosphorylation targets of p47phox, a subunit of the respiratory burst oxidase. Functions of the individual target serines as evaluated by site-directed mutagenesis. J. Clin. Invest. 96, 1499-1505.
Fickenscher,H., Hor,S., Kupers,H., Knappe,A., Wittmann,S., and Sticht,H. (2002). The interleukin-10 family of cytokines. Trends Immunol. 23, 89-96.
Fomina,A.F., Deerinck,T.J., Ellisman,M.H., and Cahalan,M.D. (2003). Regulation of membrane trafficking and subcellular organization of endocytic compartments revealed with FM1-43 in resting and activated human T cells. Exp. Cell Res. 291, 150-166.
Fu,X., Beer,D.G., Behar,J., Wands,J., Lambeth,D., and Cao,W. (2006). cAMP-response element-binding protein mediates acid-induced NADPH oxidase NOX5-S expression in Barrett esophageal adenocarcinoma cells. J. Biol. Chem. 281, 20368-20382.
Gallagher,G., Dickensheets,H., Eskdale,J., Izotova,L.S., Mirochnitchenko,O.V., Peat,J.D., Vazquez,N., Pestka,S., Donnelly,R.P., and Kotenko,S.V. (2000). Cloning, expression and initial characterization of interleukin-19 (IL-19), a novel homologue of human interleukin-10 (IL-10). Genes Immun. 1, 442-450.
Gallagher,G., Eskdale,J., Jordan,W., Peat,J., Campbell,J., Boniotto,M., Lennon,G.P., Dickensheets,H., and Donnelly,R.P. (2004). Human interleukin-19 and its receptor: a potential role in the induction of Th2 responses. Int. Immunopharmacol. 4, 615-626.
Gao,H.M., Liu,B., Zhang,W., and Hong,J.S. (2003). Critical role of microglial NADPH oxidase-derived free radicals in the in vitro MPTP model of Parkinson's disease. FASEB J. 17, 1954-1956.
Geiszt,M., Szeberenyi,J.B., Kaldi,K., and Ligeti,E. (1999). Role of different Ca2+ sources in the superoxide production of human neutrophil granulocytes. Free Radic. Biol. Med. 26, 1092-1099.
Geiszt,M., Witta,J., Baffi,J., Lekstrom,K., and Leto,T.L. (2003). Dual oxidases represent novel hydrogen peroxide sources supporting mucosal surface host defense. FASEB J. 17, 1502-1504.
Ghoreschi,K., Thomas,P., Breit,S., Dugas,M., Mailhammer,R., van,E.W., van der Zee,R., Biedermann,T., Prinz,J., Mack,M., Mrowietz,U., Christophers,E., Schlondorff,D., Plewig,G., Sander,C.A., and Rocken,M. (2003). Interleukin-4 therapy of psoriasis induces Th2 responses and improves human autoimmune disease. Nat. Med. 9, 40-46.
Goebel,W.S. and Dinauer,M.C. (2003). Gene therapy for chronic granulomatous disease. Acta Haematol. 110, 86-92.
Grandvaux,N., Soucy-Faulkner,A., and Fink,K. (2007). Innate host defense: Nox and Duox on phox's tail. Biochimie. 89, 1113-1122.
Grubb,B.R., Gabriel,S.E., Mengos,A., Gentzsch,M., Randell,S.H., Van Heeckeren,A.M., Knowles,M.R., Drumm,M.L., Riordan,J.R., and Boucher,R.C. (2006). SERCA pump inhibitors do not correct biosynthetic arrest of deltaF508 CFTR in cystic fibrosis. Am. J. Respir. Cell Mol. Biol. 34, 355-363.
Gruhne,B., Sompallae,R., Marescotti,D., Kamranvar,S.A., Gastaldello,S., and Masucci,M.G. (2009). The Epstein-Barr virus nuclear antigen-1 promotes genomic instability via induction of reactive oxygen species. Proc. Natl. Acad. Sci. U. S. A. 106, 2313-2318.
Guichard,C., Pedruzzi,E., Dewas,C., Fay,M., Pouzet,C., Bens,M., Vandewalle,A., Ogier-Denis,E., Gougerot-Pocidalo,M.A., and Elbim,C. (2005). Interleukin-8-induced priming of neutrophil oxidative burst requires sequential recruitment of NADPH oxidase components into lipid rafts. J. Biol. Chem. 280, 37021-37032.
Guzik,T.J., Chen,W., Gongora,M.C., Guzik,B., Lob,H.E., Mangalat,D., Hoch,N., Dikalov,S., Rudzinski,P., Kapelak,B., Sadowski,J., and Harrison,D.G. (2008). Calcium-dependent NOX5 nicotinamide adenine dinucleotide phosphate oxidase contributes to vascular oxidative stress in human coronary artery disease. J. Am. Coll. Cardiol. 52, 1803-1809.
Hallett,M.B. (2003). Holding back neutrophil aggression; the oxidase has potential. Clin. Exp. Immunol. 132, 181-184.
Hasegawa,H., Suzuki,K., Nakaji,S., and Sugawara,K. (1997). Analysis and assessment of the capacity of neutrophils to produce reactive oxygen species in a 96-well microplate format using lucigenin- and luminol-dependent chemiluminescence. J. Immunol. Methods. 210, 1-10.
Hayashi,F., Means,T.K., and Luster,A.D. (2003). Toll-like receptors stimulate human neutrophil function. Blood. 102, 2660-2669.
Heyworth,P.G., Cross,A.R., and Curnutte,J.T. (2003). Chronic granulomatous disease. Curr. Opin. Immunol. 15, 578-584.
Heyworth,P.G., Curnutte,J.T., Noack,D., and Cross,A.R. (1997). Hematologically important mutations: X-linked chronic granulomatous disease--an update. Blood Cells Mol. Dis. 23, 443-450.
Heyworth,P.G., Curnutte,J.T., Rae,J., Noack,D., Roos,D., van Koppen,E., and Cross,A.R. (2001). Hematologically important mutations: X-linked chronic granulomatous disease (second update). Blood Cells Mol. Dis. 27, 16-26.
Hsing,C.H., Chiu,C.J., Chang,L.Y., Hsu,C.C., and Chang,M.S. (2008). IL-19 is involved in the pathogenesis of endotoxic shock. Shock. 29, 7-15.
Huang,C.K., Zhan,L., Hannigan,M.O., Ai,Y., and Leto,T.L. (2000). P47(phox)-deficient NADPH oxidase defect in neutrophils of diabetic mouse strains, C57BL/6J-m db/db and db/+. J. Leukoc. Biol. 67, 210-215.
Hultqvist,M., Olsson,L.M., Gelderman,K.A., and Holmdahl,R. (2009). The protective role of ROS in autoimmune disease. Trends Immunol. 30, 201-208.
Inanami,O., Johnson,J.L., McAdara,J.K., Benna,J.E., Faust,L.R., Newburger,P.E., and Babior,B.M. (1998). Activation of the leukocyte NADPH oxidase by phorbol ester requires the phosphorylation of p47PHOX on serine 303 or 304. J. Biol. Chem. 273, 9539-9543.
Jackson,S.H., Gallin,J.I., and Holland,S.M. (1995). The p47phox mouse knock-out model of chronic granulomatous disease. J. Exp. Med. 182, 751-758.
Janiszewski,M., Lopes,L.R., Carmo,A.O., Pedro,M.A., Brandes,R.P., Santos,C.X., and Laurindo,F.R. (2005). Regulation of NAD(P)H oxidase by associated protein disulfide isomerase in vascular smooth muscle cells. J. Biol. Chem. 280, 40813-40819.
Johnson,J.L., Park,J.W., Benna,J.E., Faust,L.P., Inanami,O., and Babior,B.M. (1998). Activation of p47(PHOX), a cytosolic subunit of the leukocyte NADPH oxidase. Phosphorylation of ser-359 or ser-370 precedes phosphorylation at other sites and is required for activity. J. Biol. Chem. 273, 35147-35152.
Jordan,W.J., Eskdale,J., Boniotto,M., Lennon,G.P., Peat,J., Campbell,J.D., and Gallagher,G. (2005). Human IL-19 regulates immunity through auto-induction of IL-19 and production of IL-10. Eur. J. Immunol. 35, 1576-1582.
Kamiguti,A.S., Serrander,L., Lin,K., Harris,R.J., Cawley,J.C., Allsup,D.J., Slupsky,J.R., Krause,K.H., and Zuzel,M. (2005). Expression and activity of NOX5 in the circulating malignant B cells of hairy cell leukemia. J. Immunol. 175, 8424-8430.
Kang,E.M. and Malech,H.L. (2009). Advances in treatment for chronic granulomatous disease. Immunol. Res. 43, 77-84.
Kasahara,Y., Iwai,K., Yachie,A., Ohta,K., Konno,A., Seki,H., Miyawaki,T., and Taniguchi,N. (1997). Involvement of reactive oxygen intermediates in spontaneous and CD95 (Fas/APO-1)-mediated apoptosis of neutrophils. Blood. 89, 1748-1753.
Kettritz,R., Gaido,M.L., Haller,H., Luft,F.C., Jennette,C.J., and Falk,R.J. (1998). Interleukin-8 delays spontaneous and tumor necrosis factor-alpha-mediated apoptosis of human neutrophils. Kidney Int. 53, 84-91.
Kingo,K., Mossner,R., Ratsep,R., Raud,K., Kruger,U., Silm,H., Vasar,E., Reich,K., and Koks,S. (2008). Association analysis of IL20RA and IL20RB genes in psoriasis. Genes Immun. 9, 445-451.
Kiss,P.J., Knisz,J., Zhang,Y., Baltrusaitis,J., Sigmund,C.D., Thalmann,R., Smith,R.J., Verpy,E., and Banfi,B. (2006). Inactivation of NADPH oxidase organizer 1 results in severe imbalance. Curr. Biol. 16, 208-213.
Koie,T., Suzuki,K., Shimoyama,T., Umeda,T., Nakaji,S., and Sugawara,K. (2001). Effect of interferon-alpha on production of reactive oxygen species by human neutrophils. Luminescence. 16, 39-43.
Lambeth,J.D. (2007). Nox enzymes, ROS, and chronic disease: an example of antagonistic pleiotropy. Free Radic. Biol. Med. 43, 332-347.
Lambeth,J.D., Kawahara,T., and Diebold,B. (2007). Regulation of Nox and Duox enzymatic activity and expression. Free Radic. Biol. Med. 43, 319-331.
Laurindo,F.R., Fernandes,D.C., Amanso,A.M., Lopes,L.R., and Santos,C.X. (2008). Novel role of protein disulfide isomerase in the regulation of NADPH oxidase activity: pathophysiological implications in vascular diseases. Antioxid. Redox. Signal. 10, 1101-1113.
Li,H.H., Lin,Y.C., Chen,P.J., Hsiao,C.H., Lee,J.Y., Chen,W.C., Tzung,T.Y., Wu,J.C., and Chang,M.S. (2005). Interleukin-19 upregulates keratinocyte growth factor and is associated with psoriasis. Br. J. Dermatol. 153, 591-595.
Liao,S.C., Cheng,Y.C., Wang,Y.C., Wang,C.W., Yang,S.M., Yu,C.K., Shieh,C.C., Cheng,K.C., Lee,M.F., Chiang,S.R., Shieh,J.M., and Chang,M.S. (2004). IL-19 induced Th2 cytokines and was up-regulated in asthma patients. J. Immunol. 173, 6712-6718.
Lin,S.J., Huang,Y.F., Chen,J.Y., Heyworth,P.G., Noack,D., Wang,J.Y., Lin,C.Y., Chiang,B.L., Yang,C.M., Liu,C.C., and Shieh,C.C. (2002). Molecular quality control machinery contributes to the leukocyte NADPH oxidase deficiency in chronic granulomatous disease. Biochim. Biophys. Acta. 1586, 275-286.
Liu,S.Y., Tsai,M.Y., Chuang,K.P., Huang,Y.F., and Shieh,C.C. (2008). Ligand binding of leukocyte integrin very late antigen-4 involves exposure of sulfhydryl groups and is subject to redox modulation. Eur. J Immunol. 38, 410-423.
Loo,T.W., Bartlett,M.C., and Clarke,D.M. (2004). Thapsigargin or curcumin does not promote maturation of processing mutants of the ABC transporters, CFTR, and P-glycoprotein. Biochem. Biophys. Res. Commun. 325, 580-585.
Luo,H.R. and Loison,F. (2008). Constitutive neutrophil apoptosis: mechanisms and regulation. Am. J. Hematol. 83, 288-295.
Marshall,J.C., Jia,S.H., Parodo,J., and Watson,R.W. (2008). Interleukin-1beta mediates LPS-induced inhibition of apoptosis in retinoic acid-differentiated HL-60 cells. Biochem. Biophys. Res. Commun. 369, 532-538.
Munro,A.W. and Noble,M.A. (1999). Fluorescence analysis of flavoproteins. Methods Mol. Biol. 131, 25-48.
Nakamura,M., Murakami,M., Koga,T., Tanaka,Y., and Minakami,S. (1987). Monoclonal antibody 7D5 raised to cytochrome b558 of human neutrophils: immunocytochemical detection of the antigen in peripheral phagocytes of normal subjects, patients with chronic granulomatous disease, and their carrier mothers. Blood. 69, 1404-1408.
Nauseef,W.M. (1999). Quality control in the endoplasmic reticulum: lessons from hereditary myeloperoxidase deficiency. J. Lab Clin. Med. 134, 215-221.
Nauseef,W.M. (2007). Isolation of human neutrophils from venous blood. Methods Mol. Biol. 412, 15-20.
Nauseef,W.M. (2008). Biological roles for the NOX family NADPH oxidases. J. Biol. Chem. 283, 16961-16965.
Ostedgaard,L.S., Rogers,C.S., Dong,Q., Randak,C.O., Vermeer,D.W., Rokhlina,T., Karp,P.H., and Welsh,M.J. (2007). Processing and function of CFTR-DeltaF508 are species-dependent. Proc. Natl. Acad. Sci. U. S. A. 104, 15370-15375.
Otkjaer,K., Kragballe,K., Funding,A.T., Clausen,J.T., Noerby,P.L., Steiniche,T., and Iversen,L. (2005). The dynamics of gene expression of interleukin-19 and interleukin-20 and their receptors in psoriasis. Br. J. Dermatol. 153, 911-918.
Paffenholz,R., Bergstrom,R.A., Pasutto,F., Wabnitz,P., Munroe,R.J., Jagla,W., Heinzmann,U., Marquardt,A., Bareiss,A., Laufs,J., Russ,A., Stumm,G., Schimenti,J.C., and Bergstrom,D.E. (2004). Vestibular defects in head-tilt mice result from mutations in Nox3, encoding an NADPH oxidase. Genes Dev. 18, 486-491.
Papp,E., Nardai,G., Mandl,J., Banhegyi,G., and Csermely,P. (2005). FAD oxidizes the ERO1-PDI electron transfer chain: the role of membrane integrity. Biochem. Biophys. Res. Commun. 338, 938-945.
Parrish-Novak,J., Xu,W., Brender,T., Yao,L., Jones,C., West,J., Brandt,C., Jelinek,L., Madden,K., McKernan,P.A., Foster,D.C., Jaspers,S., and Chandrasekher,Y.A. (2002). Interleukins 19, 20, and 24 signal through two distinct receptor complexes. Differences in receptor-ligand interactions mediate unique biological functions. J. Biol. Chem. 277, 47517-47523.
Pollock,J.D., Williams,D.A., Gifford,M.A., Li,L.L., Du,X., Fisherman,J., Orkin,S.H., Doerschuk,C.M., and Dinauer,M.C. (1995). Mouse model of X-linked chronic granulomatous disease, an inherited defect in phagocyte superoxide production. Nat. Genet. 9, 202-209.
Porter,C.D., Kuribayashi,F., Parkar,M.H., Roos,D., and Kinnon,C. (1996). Detection of gp91-phox precursor protein in B-cell lines from patients with X-linked chronic granulomatous disease as an indicator for mutations impairing cytochrome b558 biosynthesis. Biochem. J. 315, 571-575.
Porter,C.D., Parkar,M.H., Verhoeven,A.J., Levinsky,R.J., Collins,M.K., and Kinnon,C. (1994). p22-phox-deficient chronic granulomatous disease: reconstitution by retrovirus-mediated expression and identification of a biosynthetic intermediate of gp91-phox. Blood. 84, 2767-2775.
Rada,B., Hably,C., Meczner,A., Timar,C., Lakatos,G., Enyedi,P., and Ligeti,E. (2008). Role of Nox2 in elimination of microorganisms. Semin. Immunopathol. 30, 237-253.
Rada,B.K., Geiszt,M., Van,B.R., Nemet,K., Roos,D., and Ligeti,E. (2003). Calcium signalling is altered in myeloid cells with a deficiency in NADPH oxidase activity. Clin. Exp. Immunol. 132, 53-60.
Robben,J.H., Sze,M., Knoers,N.V., and Deen,P.M. (2006). Rescue of vasopressin V2 receptor mutants by chemical chaperones: specificity and mechanism. Mol. Biol. Cell. 17, 379-386.
Robben,J.H., Sze,M., Knoers,N.V., and Deen,P.M. (2007). Functional rescue of vasopressin V2 receptor mutants in MDCK cells by pharmacochaperones: relevance to therapy of nephrogenic diabetes insipidus. Am. J. Physiol Renal Physiol. 292, F253-F260.
Robinson,J.M. (2008). Reactive oxygen species in phagocytic leukocytes. Histochem. Cell Biol. 130, 281-297.
Robinson,J.M. (2009). Phagocytic leukocytes and reactive oxygen species. Histochem. Cell Biol. 131, 465-469.
Roesler,J., Heyden,S., Burdelski,M., Schafer,H., Kreth,H.W., Lehmann,R., Paul,D., Marzahn,J., Gahr,M., and Rosen-Wolff,A. (1999). Uncommon missense and splice mutations and resulting biochemical phenotypes in German patients with X-linked chronic granulomatous disease. Exp. Hematol. 27, 505-511.
Romer,J., Hasselager,E., Norby,P.L., Steiniche,T., Thorn,C.J., and Kragballe,K. (2003). Epidermal overexpression of interleukin-19 and -20 mRNA in psoriatic skin disappears after short-term treatment with cyclosporine a or calcipotriol. J. Invest Dermatol. 121, 1306-1311.
Roos,D., de Boer,M., Kuribayashi,F., Meischl,C., Weening,R.S., Segal,A.W., Ahlin,A., Nemet,K., Hossle,J.P., Bernatowska-Matuszkiewicz,E., and Middleton-Price,H. (1996). Mutations in the X-linked and autosomal recessive forms of chronic granulomatous disease. Blood. 87, 1663-1681.
Roth,J., Yam,G.H., Fan,J., Hirano,K., Gaplovska-Kysela,K., Le,F., V, Guhl,B., Santimaria,R., Torossi,T., Ziak,M., and Zuber,C. (2008). Protein quality control: the who's who, the where's and therapeutic escapes. Histochem. Cell Biol. 129, 163-177.
Schappi,M.G., Jaquet,V., Belli,D.C., and Krause,K.H. (2008). Hyperinflammation in chronic granulomatous disease and anti-inflammatory role of the phagocyte NADPH oxidase. Semin. Immunopathol. 30, 255-271.
Segal,B.H., Romani,L., and Puccetti,P. (2009). Chronic granulomatous disease. Cell Mol. Life Sci. 66, 553-558.
Silliman,C.C., Elzi,D.J., Ambruso,D.R., Musters,R.J., Hamiel,C., Harbeck,R.J., Paterson,A.J., Bjornsen,A.J., Wyman,T.H., Kelher,M., England,K.M., McLaughlin-Malaxecheberria,N., Barnett,C.C., Aiboshi,J., and Bannerjee,A. (2003). Lysophosphatidylcholines prime the NADPH oxidase and stimulate multiple neutrophil functions through changes in cytosolic calcium. J. Leukoc. Biol. 73, 511-524.
Stasia,M.J. and Li,X.J. (2008). Genetics and immunopathology of chronic granulomatous disease. Semin. Immunopathol. 30, 209-235.
Sumimoto,H. (2008). Structure, regulation and evolution of Nox-family NADPH oxidases that produce reactive oxygen species. FEBS J. 275, 3249-3277.
Takeda,K. and Akira,S. (2005). Toll-like receptors in innate immunity. Int. Immunol. 17, 1-14.
Takeya,R., Ueno,N., Kami,K., Taura,M., Kohjima,M., Izaki,T., Nunoi,H., and Sumimoto,H. (2003). Novel human homologues of p47phox and p67phox participate in activation of superoxide-producing NADPH oxidases. J. Biol. Chem. 278, 25234-25246.
Tanaka,A.R., Kano,F., Ueda,K., and Murata,M. (2008). The ABCA1 Q597R mutant undergoes trafficking from the ER upon ER stress. Biochem. Biophys. Res. Commun. 369, 1174-1178.
Tintinger,G.R., Theron,A.J., Steel,H.C., and Anderson,R. (2001). Accelerated calcium influx and hyperactivation of neutrophils in chronic granulomatous disease. Clin. Exp. Immunol. 123, 254-263.
Tsukahara,Y., Lian,Z., Zhang,X., Whitney,C., Kluger,Y., Tuck,D., Yamaga,S., Nakayama,Y., Weissman,S.M., and Newburger,P.E. (2003). Gene expression in human neutrophils during activation and priming by bacterial lipopolysaccharide. J. Cell Biochem. 89, 848-861.
Ushio-Fukai,M. and Nakamura,Y. (2008). Reactive oxygen species and angiogenesis: NADPH oxidase as target for cancer therapy. Cancer Lett. 266, 37-52.
Valente,A.J., El,J.A., Epperson,T.K., Gamez,M.J., Pearson,D.W., and Clark,R.A. (2007). NOX1 NADPH oxidase regulation by the NOXA1 SH3 domain. Free Radic. Biol. Med. 43, 384-396.
Varsanyi,M., Szarka,A., Papp,E., Makai,D., Nardai,G., Fulceri,R., Csermely,P., Mandl,J., Benedetti,A., and Banhegyi,G. (2004). FAD transport and FAD-dependent protein thiol oxidation in rat liver microsomes. J. Biol. Chem. 279, 3370-3374.
Vigone,M.C., Fugazzola,L., Zamproni,I., Passoni,A., Di,C.S., Chiumello,G., Persani,L., and Weber,G. (2005). Persistent mild hypothyroidism associated with novel sequence variants of the DUOX2 gene in two siblings. Hum. Mutat. 26, 395.
Ward,R.A., Nakamura,M., and McLeish,K.R. (2000). Priming of the neutrophil respiratory burst involves p38 mitogen-activated protein kinase-dependent exocytosis of flavocytochrome b558-containing granules. J. Biol. Chem. 275, 36713-36719.
Wei,C.C., Chen,W.Y., Wang,Y.C., Chen,P.J., Lee,J.Y., Wong,T.W., Chen,W.C., Wu,J.C., Chen,G.Y., Chang,M.S., and Lin,Y.C. (2005). Detection of IL-20 and its receptors on psoriatic skin. Clin. Immunol. 117, 65-72.
Welch,W.J. (2004). Role of quality control pathways in human diseases involving protein misfolding. Semin. Cell Dev. Biol. 15, 31-38.
Whyte,M.K., Hardwick,S.J., Meagher,L.C., Savill,J.S., and Haslett,C. (1993). Transient elevations of cytosolic free calcium retard subsequent apoptosis in neutrophils in vitro. J. Clin. Invest. 92, 446-455.
Williams,D.A., Tao,W., Yang,F., Kim,C., Gu,Y., Mansfield,P., Levine,J.E., Petryniak,B., Derrow,C.W., Harris,C., Jia,B., Zheng,Y., Ambruso,D.R., Lowe,J.B., Atkinson,S.J., Dinauer,M.C., and Boxer,L. (2000). Dominant negative mutation of the hematopoietic-specific Rho GTPase, Rac2, is associated with a human phagocyte immunodeficiency. Blood. 96, 1646-1654.
Wyche,K.E., Wang,S.S., Griendling,K.K., Dikalov,S.I., Austin,H., Rao,S., Fink,B., Harrison,D.G., and Zafari,A.M. (2004). C242T CYBA polymorphism of the NADPH oxidase is associated with reduced respiratory burst in human neutrophils. Hypertension. 43, 1246-1251.
Yamauchi,A., Yu,L., Potgens,A.J., Kuribayashi,F., Nunoi,H., Kanegasaki,S., Roos,D., Malech,H.L., Dinauer,M.C., and Nakamura,M. (2001). Location of the epitope for 7D5, a monoclonal antibody raised against human flavocytochrome b558, to the extracellular peptide portion of primate gp91phox. Microbiol. Immunol. 45, 249-257.
Yoshida,L.S., Saruta,F., Yoshikawa,K., Tatsuzawa,O., and Tsunawaki,S. (1998). Mutation at histidine 338 of gp91(phox) depletes FAD and affects expression of cytochrome b558 of the human NADPH oxidase. J. Biol. Chem. 273, 27879-27886.
Yu,L., DeLeo,F.R., Biberstine-Kinkade,K.J., Renee,J., Nauseef,W.M., and Dinauer,M.C. (1999). Biosynthesis of flavocytochrome b558 . gp91(phox) is synthesized as a 65-kDa precursor (p65) in the endoplasmic reticulum. J. Biol. Chem. 274, 4364-4369.
Zamproni,I., Grasberger,H., Cortinovis,F., Vigone,M.C., Chiumello,G., Mora,S., Onigata,K., Fugazzola,L., Refetoff,S., Persani,L., and Weber,G. (2008). Biallelic inactivation of the dual oxidase maturation factor 2 (DUOXA2) gene as a novel cause of congenital hypothyroidism. J. Clin. Endocrinol. Metab. 93, 605-610.
Zhang,X., Kluger,Y., Nakayama,Y., Poddar,R., Whitney,C., DeTora,A., Weissman,S.M., and Newburger,P.E. (2004). Gene expression in mature neutrophils: early responses to inflammatory stimuli. J. Leukoc. Biol. 75, 358-372.
Zhu,Y., Marchal,C.C., Casbon,A.J., Stull,N., von,L.K., Knaus,U.G., Jesaitis,A.J., McCormick,S., Nauseef,W.M., and Dinauer,M.C. (2006). Deletion mutagenesis of p22phox subunit of flavocytochrome b558: identification of regions critical for gp91phox maturation and NADPH oxidase activity. J. Biol. Chem. 281, 30336-30346.