Anti-IL-13 monoclonal antibody inhibits airway hyperresponsiveness, inflammation and airway remodeling

Yang, Gui-Zhen; Volk, A. Paige Davis; Petley, Ted; Emmell, Eva; Giles‐Komar, Jill; Shang, Xiaozhou; Li, Jian; Das, Anuk; Shealy, Dave; Griswold, Don E.; Li, Li

doi:10.1016/j.cyto.2004.08.007

Cited by 170 publications

(120 citation statements)

References 43 publications

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“…Our results collectively suggest that blockade of IL-13 reduces proinflammatory cytokine expression, which results in neuronal survival in the hippocampus in vivo. Our data are strongly supported by earlier reports that treatment with an anti-IL-13 mAb inhibits expression of cytokines and chemokines, such as TNF-␣ and MIP-1␣, in a mouse asthma model (34,35).…”

Section: Discussionsupporting

confidence: 81%

“…In a mouse asthma model, treatment with an anti-IL-13 mAb prevented progression of inflammation by inhibiting the expression of cytokines and chemokines, such as TNF-␣ and MIP-1␣ (34,35). In addition, in endothelial cells, IL-13 induced NADPH oxidase activation and consequent production of ROS (36), possibly leading to oxidative damage and eventual cell death.…”

Section: Discussionmentioning

confidence: 99%

“…Whereas several studies have reported beneficial effects of IL-13, such as increased survival of mice in an experimental model of sepsis (33), harmful effects of IL-13 are also documented. For instance, in a mouse asthma model, allergic airway inflammation is inhibited by treatment with an anti-IL-13 mAb (34,35). Additionally, in endothelial cells, IL-13 induces ROS production via activation of NADPH oxidase (36).…”

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confidence: 99%

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IL-13-Induced Oxidative Stress via Microglial NADPH Oxidase Contributes to Death of Hippocampal Neurons In Vivo

Park

Baik

Jin

2009

The Journal of Immunology

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In the present study, we investigated the effects of IL-13, a well-known anti-inflammatory cytokine, on the thrombin-treated hippocampus in vivo. NeuN immunohistochemistry and Nissl staining revealed significant loss of hippocampal CA1 neurons upon intrahippocampal injection of thrombin. This neurotoxicity was accompanied by substantial microglial activation, as evident from OX-42 immunohistochemistry results. In parallel, Western blot analysis and hydroethidine histochemistry disclosed activation of NADPH oxidase, generation of reactive oxygen species, and oxidative damage in the hippocampal CA1 area showing hippocampal neuron degeneration. Interestingly, immunohistochemical and biochemical experiments showed that intrahippocampal injection of thrombin increased IL-13 immunoreactivity and IL-13 levels as early as 8 h after thrombin, reaching a peak at 7 days, which was maintained up to 14 days. Moreover, double-label immunohistochemistry revealed IL-13 immunoreactivity exclusively in activated microglia. IL-13-neutralizing Abs significantly rescued CA1 hippocampal neurons from thrombin neurotoxicity. In parallel, neutralization of IL-13 inhibited activation of NADPH oxidase, reactive oxygen species production, and oxidative damage. Additionally, IL-13 neutralization suppressed the expression of inducible NO synthase and several proinflammatory cytokines. To our knowledge, the present study is the first to show that IL-13 triggers microglial NADPH oxidase-derived oxidative stress, leading to the degeneration of hippocampal neurons in vivo, as occurs in cases of Alzheimer’s disease.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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IL-13-Induced Oxidative Stress via Microglial NADPH Oxidase Contributes to Death of Hippocampal Neurons In Vivo

Park

Baik

Jin

2009

The Journal of Immunology

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“…IL-13 is a pleiotropic cytokine produced mainly by T cells and is critical for the development of airway hyperresponsiveness (AHR) associated with allergen exposure [18]. It has indeed been reported that treatment of mice with anti-IL-13 mAb inhibited AHR [19,20] and that Il-13-induced airway inflammation might involve a direct effect on airway smooth muscles [21]. Our results strongly suggest that IL-13 production is intrinsically different in the two mouse strains and accounts for the increased bronchial hyperresponsiveness in BALB/c mice.…”

Section: Discussionmentioning

confidence: 99%

Mouse models of asthma: a comparison between C57BL/6 and BALB/c strains regarding bronchial responsiveness, inflammation, and cytokine production

et al. 2009

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Objective Animal models of asthma mimic major features of human disease. Since the genetic background of experimental animals might affect hyperresponsiveness and inflammation, we studied its potential influence and the mechanisms leading to differences in strains. MethodsWe applied a mouse model of allergic asthma to BALB/c and C57BL/6 mice.Results BALB/c mice displayed greater levels of airway reactivity to methacholine than C57BL/6 mice. Moreover, BALB/c mice exhibited higher numbers of mast cells in lung tissue when compared to C57BL/6. On the contrary, eosinophil and neutrophil counts in bronchoalveolar lavage fluid (BALF) as well as peribronchial eosinophilia were greater in C57BL/6. IL (Interleukin)-4, IL-5, IL-13, and CCL11 levels measured in wholelung extracts were higher in BALB/c, while, in sharp contrast, CCL11 and CCL5 levels were higher in BALF of C57BL/6 mice. ConclusionsWe observed phenotypic differences between C57BL/6 and BALB/c mice in an asthma model with different distributions of pro-inflammatory cytokines and inflammatory cells.

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“…The type II cytokine hypothesis suggests that these responses are linked in a cause and effect fashion and that fibrosis occurs when inflammation shifts in a Th2 direction (41). IL-13 is felt to be the major Th2 cell-derived fibrogenic effector in these responses (8,(42)(43)(44). This can be readily appreciated in recent studies that highlighted the importance of IL-13 and the impressive induction of genes that contribute to healing and scaring in type II but not in type I granulomatous responses (43,45).…”

Section: Discussionmentioning

confidence: 99%

Role of 5-Lipoxygenase in IL-13-Induced Pulmonary Inflammation and Remodeling

Shim

Zhu

Zheng

et al. 2006

The Journal of Immunology

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Exaggerated levels of IL-13 and leukotriene (LT) pathway activation frequently coexist at sites of Th2 inflammation and in tissue fibrotic responses. However, the relationship(s) between the IL-13 and LTs in these responses have not been defined. We hypothesized that the 5-lipoxygenase (5-LO) pathway of LT metabolism plays an important role in the pathogenesis of IL-13-induced chronic inflammation and remodeling. To test this hypothesis, we evaluated the effects of IL-13 on components of the 5-LO metabolic and activation pathways. We also compared the effects of transgenic IL-13 in C57BL/6 mice with wild-type and null 5-LO genetic loci. These studies demonstrate that IL-13 increases the levels of mRNA encoding cytosolic phospholipase A2, LTA4 hydrolase, and 5-LO-activating protein without altering the expression of 5-LO, LTC4 synthase, LTB4 receptors 1 and 2, and cysteinyl-LT receptors 1 and 2. They also demonstrate that this activation is associated with the enhanced accumulation of LTB4 but not of cysteinyl-LTs. Furthermore, they demonstrate that this stimulation plays a critical role in the pathogenesis of IL-13-induced inflammation, tissue fibrosis, and respiratory failure-induced death while inhibiting alveolar remodeling. Lastly, mechanistic insights are provided by demonstrating that IL-13-induced 5-LO activation is required for optimal stimulation and activation of TGF-β1 and the inhibition of matrix metalloproteinase-12. When viewed in combination, these studies demonstrate that 5-LO plays an important role in IL-13-induced inflammation and remodeling.

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Anti-IL-13 monoclonal antibody inhibits airway hyperresponsiveness, inflammation and airway remodeling

Cited by 170 publications

References 43 publications

IL-13-Induced Oxidative Stress via Microglial NADPH Oxidase Contributes to Death of Hippocampal Neurons In Vivo

IL-13-Induced Oxidative Stress via Microglial NADPH Oxidase Contributes to Death of Hippocampal Neurons In Vivo

Mouse models of asthma: a comparison between C57BL/6 and BALB/c strains regarding bronchial responsiveness, inflammation, and cytokine production

Role of 5-Lipoxygenase in IL-13-Induced Pulmonary Inflammation and Remodeling

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