Inhibition of Human Neutrophil IL-8 Production by Hydrogen Peroxide and Dysregulation in Chronic Granulomatous Disease

Lekstrom-Himes, Julie; Kuhns, Douglas B.; Alvord, W. Gregory; Gallin, John I.

doi:10.4049/jimmunol.174.1.411

Cited by 86 publications

(63 citation statements)

References 30 publications

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“…The available reports invariably describe increased inflammatory reactions in CGD cells/patients [3,[38][39][40], and a recent microarray study described up-regulation of various proinflammatory genes in unstimulated CGD cells compared to controls [41]. Thus, the data presented in our work are consistent with these published studies and suggest that ROS exhibit a dampening effect on inflammatory reactions, which fits very well with clinical data on exuberant inflammatory responses in CGD patients [4,42,43].…”

Section: Discussionsupporting

confidence: 82%

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

et al. 2007

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Reactive 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-jB, 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-jB 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 (gp91 phox-/-), but not in control cells in the presence of NADPHoxidase inhibitor diphenyleneiodonium, probably reflecting NADPH-oxidase-independent effects of the inhibitor. Furthermore, we show that the major steps involved in NFjB activation were intact in human CGD cells. These data indicate that ROS were nonessential for activation of NF-jB and their production may even attenuate inflammation.

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Section: Discussionsupporting

confidence: 82%

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

et al. 2007

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“…In contrast, our findings of the inhibitory effects of ROS on caspase-1 activation agree with a proinflammatory state in CGD, because we found that the release of mature IL-1β was normal and after certain stimuli even increased in cells of CGD patients. Our data do not stand alone; they are in line with several previous studies that have demonstrated consistent up-regulation of various proinflammatory cytokines in cells isolated from CGD patients (27)(28)(29)(30). Unexpectedly, whereas we found that primary monocytes from healthy volunteers did not produce IL-1β in response to uric acid alone, monocytes from CGD patients secreted substantial amounts of IL-1β.…”

Section: Discussionsupporting

confidence: 78%

Reactive oxygen species–independent activation of the IL-1β inflammasome in cells from patients with chronic granulomatous disease

Veerdonk

Smeekens

Joosten

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

228

166

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Humans with chronic granulomatous diseases (CGDs) due to mutations in p47-phox have defective NADPH activity and thus cannot generate NADPH-dependent reactive oxygen species (ROS). The role of ROS in inflammation is controversial; some in vitro studies suggest that ROS are crucial for secretion of IL-1β via inflammasome activation, whereas mice defective for ROS and patients with CGD have a proinflammatory phenotype. In this study, we evaluated activation of the IL-1β inflammasome in cells from CGD patients. In contrast to previous studies using the small molecule diphenylene iodonium (DPI) as a ROS inhibitor, we found no decrease in either caspase-1 activation or secretion of IL-1β and IL-18 in primary CGD monocytes. Moreover, activation of CGD monocytes by uric acid crystals induced a 4-fold higher level of IL-1β secretion compared with that seen in monocytes from unaffected subjects, and this increase was not due to increased synthesis of the IL-1β precursor. In addition, Western blot analysis of CGD cells revealed that caspase-1 activation was not decreased, but rather was increased compared with control cells. Examination of the effects exerted by the inhibition of ROS activity by DPI revealed that the decrease in IL-1β secretion by DPI was actually due to inhibition of IL-1β gene expression. Thus, inconsistent with the proinflammatory role of ROS, the present findings support the concept that ROS likely dampen inflammasome activation. The absence of ROS in CGD monocytes may explain the presence of an inflammatory phenotype characterized by granulomas and inflammatory bowel disease occurring in CGD patients.antioxidants | colitis | gout | inflammation | uric acid

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“…This view correlates with previous observations that the genetic defect of p47-PHOX enhances autoimmune encephalomyelitis and arthritis in animal models (Hultqvist et al, 2004) and leads to chronic non-infectious inflammation in chronic granulomatous disease (Morgenstern et al, 1997). Additional support for this hypothesis comes from a recently published study showing that p47-PHOX-mediated ROS negatively regulate expression of IL-8 and IL-1␤ in human neutrophils (Lekstrom-Himes et al, 2005). However, the mechanism by which ROS modulate inflammation appears to be more complex.…”

Section: Discussionsupporting

confidence: 75%

Suppression of Microglial Inflammatory Activity by Myelin Phagocytosis: Role of p47-PHOX-Mediated Generation of Reactive Oxygen Species

Liu¹,

Hao²,

Letièmbre³

et al. 2006

J. Neurosci.

112

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Multiple sclerosis (MS) is pathologically characterized by inflammatory demyelination and neuronal injury. Although phagocytosis of myelin debris by microglia and macrophages in acute MS lesions is well documented, its pathophysiological significance is unclear. Using real-time quantitative PCR, flow cytometry, ELISA, and reactive oxygen species (ROS) measurement assays, we demonstrated that phagocytosis of myelin modulates activation of microglial cells prestimulated by interferon-␥ (IFN-␥) or a combination of IFN-␥ and lipopolysaccharide with a biphasic temporal pattern, i.e., enhanced production of proinflammatory mediators during the first phase (Յ6 h), followed by suppression during the second (6 -24 h) phase. In this second phase, myelin phagocytosis leads to an enhanced release of prostaglandin E2 and ROS in microglia, whereas the production of anti-inflammatory cytokines (particularly interleukin-10) remains unchanged. Suppression of inflammatory microglial activation by myelin phagocytosis was reversed by treatment with superoxide dismutase and catalase, by inhibition of the NADPH-oxidase complex, or by specific knockdown of the NADPH-oxidase-required adaptor p47-phagocyte oxidase (PHOX). Furthermore, we observed that myelin phagocytosis destabilized tumor necrosis factor-␣ and interferon-induced protein-10 mRNA through an adenine-uridine-rich elements-involved mechanism, which was reversed by blocking the function of NADPH-oxidase complex. We conclude that phagocytosis of myelin suppresses microglial inflammatory activities via enhancement of p47-PHOX-mediated ROS generation. These results suggest that intervention in ROS generation could represent a novel therapeutic strategy to reduce neuroinflammation in MS.

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Inhibition of Human Neutrophil IL-8 Production by Hydrogen Peroxide and Dysregulation in Chronic Granulomatous Disease

Cited by 86 publications

References 30 publications

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

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

Reactive oxygen species–independent activation of the IL-1β inflammasome in cells from patients with chronic granulomatous disease

Suppression of Microglial Inflammatory Activity by Myelin Phagocytosis: Role of p47-PHOX-Mediated Generation of Reactive Oxygen Species

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