Enhanced inflammatory responses of chronic granulomatous disease leukocytes involve ROS‐independent activation of NF‐κB

European Journal of Immunology - Tập 37 Số 4 - Trang 1087-1096 - 2007
Johan Bylund1,2, Kelly L. MacDonald3,1, Kelly L. Brown3, Piotr Mydel4,2, L. Vincent Collins2, Robert E. W. Hancock3, David P. Speert3,1
1Department of Pediatrics, University of British Columbia, Child and Family Research Institute, Vancouver, British Columbia, Canada
2Department of Rheumatology and Inflammation Research, Göteborg University, Göteborg, Sweden
3Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada
4Department of Microbiology, Faculty of Biotechnology, Jagiellonian University, Krakow, Poland

Tóm tắt

AbstractReactive oxygen species (ROS) generated by the cellular NADPH‐oxidase are crucial for phagocytic killing of ingested microbes and have been implicated as signaling molecules in various processes. For example, ROS are thought to be involved in activation of the transcription factor NF‐κB, central for mediating production of proinflammatory cytokines in response to inflammatory stimuli. Several studies have demonstrated that inhibitors of the NADPH‐oxidase interfere with NF‐κB activation and production of proinflammatory cytokines. Curiously, patients with chronic granulomatous disease (CGD), an immunodeficiency characterized by an inability to produce ROS, are not only predisposed to severe infections, but also frequently develop various inflammatory complications indicative of exaggerated inflammatory responses. Here, we show that human CGD leukocytes display a hyperinflammatory phenotype with increased production of proinflammatory cytokines in response to stimulation with Toll‐like receptor agonists. The hyperinflammatory phenotype was also evident in mononuclear cells from CGD mice (gp91phox–/–), but not in control cells in the presence of NADPH‐oxidase inhibitor diphenyleneiodonium, probably reflecting NADPH‐oxidase‐independent effects of the inhibitor. Furthermore, we show that the major steps involved in NF‐κB activation were intact in human CGD cells. These data indicate that ROS were nonessential for activation of NF‐κB and their production may even attenuate inflammation.

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Tài liệu tham khảo

10.1097/00005792-200005000-00003

10.1007/0-387-25342-4_5

10.1007/BF00917259

10.1097/00005792-200005000-00004

10.1084/jem.182.3.751

10.1084/jem.185.2.207

10.1038/ng0295-202

10.1016/S0952-7915(03)00080-3

10.1146/annurev.immunol.16.1.225

10.1038/ni1196

10.1089/ars.2005.7.395

10.4049/jimmunol.172.4.2522

10.1172/JCI18696

10.1016/S0891-5849(96)00501-1

10.4049/jimmunol.172.3.1801

10.4049/jimmunol.166.12.7514

10.1084/jem.175.5.1181

10.1016/S0006-291X(03)00308-5

10.1002/glia.20017

10.1016/j.biocel.2005.02.004

10.1016/S0022-1759(99)00146-5

10.1038/365182a0

10.2174/1389450003349056

10.1074/jbc.M311192200

10.1006/clin.1993.1078

10.1046/j.1365-2249.2001.01447.x

Kasahara Y., 1997, Involvement of reactive oxygen intermediates in spontaneous and CD95 (Fas/APO‐1)‐mediated apoptosis of neutrophils., Blood, 89, 1748, 10.1182/blood.V89.5.1748

10.4049/jimmunol.174.6.3562

10.1189/jlb.71.5.775

10.1189/jlb.1202599

10.1046/j.1365-2249.1996.d01-755.x

10.1038/ng1058

10.1073/pnas.0604571103

10.1189/jlb.0203082

10.1089/ars.1999.1.2-181

10.1016/S0006-2952(99)00296-8

10.1093/emboj/cdg332

10.1080/00365540310013009

10.1016/j.imlet.2004.04.016

10.4049/jimmunol.174.1.411

10.4049/jimmunol.172.1.636

10.1111/j.1365-2559.2005.02258.x

10.1097/00005176-200305000-00006

10.1038/nature03963

10.1161/01.RES.0000188210.72062.10

10.1016/S0891-5849(02)00840-7

10.1007/BF00916817

10.1111/j.1365-2257.1994.tb00384.x

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European Journal of Immunology

Tập 37 Số 4

1087-1096

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