Effects of Anticytokine Therapy in a Mouse Model of Chronic Asthma

Kumar, Rakesh K.; Herbert, Cristan; Webb, Dianne C.; Li, Lily; Foster, Paul S.

doi:10.1164/rccm.200405-681oc

Cited by 126 publications

(109 citation statements)

References 58 publications

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“…Our data suggest that AM are important producers of this cytokine. IL-13 was increased in sensitized rats (1O) compared with unsensitized rats (1S), but the transfer of unsensitized AM to sensitized rats (3O) did not decrease the IL-13 level, suggesting that IL-13 is not involved in airway hyperresponsiveness after allergen challenge, as shown in studies using anti-IL-13 antibody (31,33). Thus the modulation of airway hyperresponsiveness in our model may be induced by other Th2 cytokines.…”

Section: Discussionmentioning

confidence: 57%

Antigen sensitization modulates alveolar macrophage functions in an asthma model

Careau¹,

Proulx²,

Pouliot³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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-We have previously demonstrated that adoptive transfer of alveolar macrophages from allergy-resistant rats to alveolar macrophage-depleted allergic rats prevents airway hyperresponsiveness development, suggesting an important role for alveolar macrophages in asthma pathogenesis. Given that ovalbumin sensitization can modulate alveolar macrophage cytokine production, we investigated the role of sensitized and unsensitized alveolar macrophages in an asthma model. Alveolar macrophages from unsensitized or sensitized Brown Norway rats were transferred to alveolar macrophage-depleted sensitized rats 24 h before allergen challenge. Airway responsiveness to methacholine and airway inflammation were measured the following day. Methacholine concentration needed to increase lung resistance by 200% was significantly higher in alveolar macrophage-depleted sensitized rats that received unsensitized alveolar macrophages compared with alveolar macrophage-depleted sensitized rats that received sensitized alveolar macrophages. Tumor necrosis factor levels in bronchoalveolar lavage fluid of sensitized rats that received unsensitized alveolar macrophages were significantly lower compared with rats that received sensitized alveolar macrophages. Interestingly, alveolar macrophages of unsensitized animals showed higher phagocytosis activity compared with alveolar macrophages of sensitized rats, suggesting that sensitization modulates alveolar macrophage phagocytosis function. Our data suggest an important role of allergen sensitization on alveolar macrophage function in asthma pathogenesis. airway hyperresponsiveness; cytokine; phagocytosis THE INCIDENCE OF allergic respiratory diseases increased dramatically over the last two decades. The genetic predisposition to develop asthma is now well recognized (20). Numerous studies have also shown the importance of inflammatory cells, such as mast cells, lymphocytes, eosinophils, and neutrophils, as well as Th2 type cytokines in asthma (6,19,32). Interleukin (IL)-4 and IL-13, two Th2 cytokines, are important in immunoglobulin (Ig) class switching to IgE, whereas IL-4 and IL-10 play a crucial role in Th2 cell commitment (9,16,50). In contrast, Th1 cytokines (interferon-␥ and IL-12) protect against asthma development in children (48). Other cytokines, such as tumor necrosis factor (TNF), have been demonstrated to amplify the effect of asthmatic inflammation (29,42). Recently, a role of regulatory T cells (Th3 cells, T R cells, CD4 ϩ CD25 ϩ cells, and natural killer T cells) has been suggested in the control of asthma and allergy, but the specific mechanisms are still unknown (2).Alveolar macrophages (AM) are predominant immune effector cells in the alveolar spaces and conducting airways and play a key role in the immunological homeostasis of the lung (8, 30, 43). Although they are well known to suppress T cell activation and antigen presentation activities of dendritic cells (22,41), their role in asthma is still debated. Using the liposome-mediated macrophage suicide technique (47), we have...

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Section: Discussionmentioning

confidence: 57%

Antigen sensitization modulates alveolar macrophage functions in an asthma model

Careau¹,

Proulx²,

Pouliot³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…8). Although allergic asthma has been considered a Th2-driven disease, increased IFN-␥ production has been reported in human studies (37) and in mouse models (38). Although the Th1 cytokine IFN-␥ was overproduced in GM-CSF Ϫ/Ϫ mice, the Th2 cytokines IL-4 and IL-13 were not reduced (Fig.…”

Section: Discussionmentioning

confidence: 86%

Granulocyte-Macrophage Colony-Stimulating Factor Is Required for Bronchial Eosinophilia in a Murine Model of Allergic Airway Inflammation

Rolph

Hansbro

et al. 2008

The Journal of Immunology

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GM-CSF plays an important role in inflammation by promoting the production, activation, and survival of granulocytes and macrophages. In this study, GM-CSF knockout (GM-CSF−/−) mice were used to investigate the role of GM-CSF in a model of allergic airway inflammation. In allergic GM-CSF−/− mice, eosinophil recruitment to the airways showed a striking pattern, with eosinophils present in perivascular areas, but almost completely absent in peribronchial areas, whereas in wild-type mice, eosinophil infiltration appeared in both areas. In the GM-CSF−/− mice, mucus production in the airways was also reduced, and eosinophil numbers were markedly reduced in the bronchoalveolar lavage (BAL)3 fluid. IL-5 production was reduced in the lung tissue and BAL fluid of GM-CSF−/− mice, but IL-4 and IL-13 production, airway hyperresponsiveness, and serum IgE levels were not affected. The presence of eosinophils in perivascular but not peribronchial regions was suggestive of a cell migration defect in the airways of GM-CSF−/− mice. The CCR3 agonists CCL5 (RANTES) and CCL11 (eotaxin-1) were expressed at similar levels in GM-CSF−/− and wild-type mice. However, IFN-γ mRNA and protein were increased in the lung tissue and BAL fluid in GM-CSF−/− mice, as were mRNA levels of the IFN-γ-inducible chemokines CXCL9 (Mig), CXCL10 (IP-10), and CXCL11 (I-Tac). Interestingly, these IFN-γ-inducible chemokines are natural antagonists of CCR3, suggesting that their overproduction in GM-CSF−/− mice contributes to the lack of airway eosinophils. These findings demonstrate distinctive abnormalities to a model of allergic asthma in the absence of GM-CSF.

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“…In human airways, expression of IL-13 is elevated in the bronchial mucosa of atopic asthmatics compared with nonasthmatics (1) and further up-regulated in response to allergen provocation (2). Studies in mouse models indicate that IL-13 plays a key role in eosinophil recruitment, goblet cell hyperplasia, airway hyperresponsiveness, and some aspects of airway remodeling (3)(4)(5)(6)(7)(8). Although involvement of IL-13 in pathways regulating allergic airways disease is well characterized, recent work in our laboratory has focused on the way in which IL-4 and IL-13 interact to modulate initiation of immune processes in the allergic lung.…”

mentioning

confidence: 99%

Ym1/2 Promotes Th2 Cytokine Expression by Inhibiting 12/15(S)-Lipoxygenase: Identification of a Novel Pathway for Regulating Allergic Inflammation

Cai

Kumar

Zhou

et al. 2009

The Journal of Immunology

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The Ym1/2 lectin is expressed abundantly in the allergic mouse lung in an IL-13-dependent manner. However, the role of Ym1/2 in the development of allergic airways disease is largely unknown. In this investigation, we show that treatment of mice with anti-Ym1/2 Ab during induction of allergic airways disease attenuated mediastinal lymph node production of IL-5 and IL-13. Ym1/2 was found to be expressed by dendritic cells (DCs) in an IL-13-dependent manner and supplementation of DC/CD4+ T cell cocultures with Ym1/2 enhanced the ability of IL-13−/− DCs to stimulate the secretion of IL-5 and IL-13. Affinity chromatography identified 12/15(S)-lipoxygenase (12/15-LOX) as a Ym1/2-interacting protein and functional studies suggested that Ym1/2 promoted the ability of DCs to stimulate cytokine production by inhibiting 12/15-LOX-mediated catalysis of 12-hydroxyeicosatetraenoic acid (12(S)-HETE). Treatment of DC/CD4+ T cell cultures with the 12/15-LOX inhibitor baicalein enhanced, whereas 12(S)-HETE inhibited the production of Th2 cytokines. Notably, delivery of 12(S)-HETE to the airways of mice significantly attenuated the development of allergic airways inflammation and the production of IL-5 and IL-13. In summary, our results suggest that production of Ym1/2 in response to IL-13 promotes Th2 cytokine production and allergic airways inflammation by inhibiting the production of 12(S)-HETE by 12/15-LOX.

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Effects of Anticytokine Therapy in a Mouse Model of Chronic Asthma

Cited by 126 publications

References 58 publications

Antigen sensitization modulates alveolar macrophage functions in an asthma model

Antigen sensitization modulates alveolar macrophage functions in an asthma model

Granulocyte-Macrophage Colony-Stimulating Factor Is Required for Bronchial Eosinophilia in a Murine Model of Allergic Airway Inflammation

Ym1/2 Promotes Th2 Cytokine Expression by Inhibiting 12/15(S)-Lipoxygenase: Identification of a Novel Pathway for Regulating Allergic Inflammation

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