The Role of IL-13 in Established Allergic Airway Disease

Taube, Christian; Duez, Catherine; Cui, Zhi Hua; Takeda, Katsuyuki; Rha, Yeong Ho; Park, Jung Won; Balhorn, Annette; Donaldson, Debra D.; Dakhama, Azzeddine; Gelfand, Erwin W.

doi:10.4049/jimmunol.169.11.6482

Cited by 169 publications

(153 citation statements)

References 44 publications

(66 reference statements)

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“…50 In experimental asthma models, airway hyperreactivity accompanied by high levels of IL-4 and IL-5 secretion can be induced in intact but not IL-13À/À mice. 51,52 Sensitized animals can be protected by treatment with IL-13Ra-chain constructs, 53 and although the IL-4Ra-chain may be involved, this is disputed. 46,49 Mice whose Th1 system is crippled by the genetic disruption of T-bet expression develop spontaneous asthma-like disease, which is accompanied by high numbers of CD44 and CD69 bright CD4 þ T cells; again, this condition can be ameliorated by the direct blockade of IL-13.…”

Section: Discussionmentioning

confidence: 99%

Human interferon lambda-1 (IFN-λ1/IL-29) modulates the Th1/Th2 response

et al. 2007

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Interferon lambda-1 (IFN-l1/IL-29) is a member of the Type-III interferon family, which contains three ligands: IFN-l1, 2 and 3. These three ligands use the same unique heterodimeric receptor composed of CRF2-12 (IFN-l-R1/IL-28Ra) and CRF2-4 (IL10-R-b) chains. Like their close relatives, the Type-I interferons, IFN-l1, 2 and 3, promote the phosphorylation of STAT1 and STAT2, induce the ISRE3 complex, elevate OAS and MxA expression and exhibit antiviral activity in vitro. Their use of the IL10-R-b chain and their ability to phosphorylate STAT3, STAT4 and STAT5 suggested that they may also exhibit immunomodulatory activity; their antiviral action led us to hypothesize that this activity might be directed toward the Th1/Th2 system. Here, we have demonstrated that IFN-l1 altered the activity of Th cells in three separate experimental systems: (i) mitogen stimulation, (ii) mixed-lymphocyte reaction (MLR) and (iii) stimulation of naive T cells by monocyte-derived dendritic cells (mDC). In Con-A stimulation assays, the inclusion of IFN-l1 consistently led to markedly diminished levels of secreted interleukin (IL-13) with occasional coincident, modest elevation of secreted IFN-g. IL-13 secretion was 100-fold more sensitive to IFN-l1 than was IFN-g secretion. These observations were also made in the allogeneic two-way MLR. IFN-l1 was able to alter cytokine-mediated Th biasing and when naive T cells were exposed to allogeneic mDC that had been matured in the presence of IFN-l1, secreted IL-13 was again markedly and consistently reduced, whereas secreted IFN-g was largely unaltered. These functions were independent of IL-10. Our data support a hitherto unsuspected role for IFN-l1 in modulating the development of Th1 and Th2 cells, with an apparent emphasis on the diminution of IL-13 secretion.

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Section: Discussionmentioning

confidence: 99%

Human interferon lambda-1 (IFN-λ1/IL-29) modulates the Th1/Th2 response

et al. 2007

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“…Activation of both IL-13 and IL-4 membrane-bound heterodimeric receptors induces receptor molecule dimerization and activation of the Janus family members of inner membrane-bound tyrosine kinases, which then phosphorylate and initiate the nuclear transport of STAT-6 transcription factors [9]. However, studies in murine models of asthma have indicated that IL-13 rather than IL-4 appears to be critical for the development of allergic airway inflammation, hyperresponsiveness and matrix remodeling in asthma [30][31][32][33][34][35]. In the present study, we observed that overexpression of c-Maf, in the absence of a coincident overexpression of GATA-3, but in the presence of IL-2, down-regulates IL-13 but not IL-4 production in developing and polarized lung CD4 + T cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

A stage‐specific functional role of the leucine zipper transcription factor c‐Maf in lung Th2 cell differentiation

Hausding¹,

Lehr³

et al. 2004

Eur J Immunol

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The transcription factor c-Maf controls IL-4 gene expression in CD4 + T cells, and its expression is up-regulated in human asthmatic airways after allergen challenge. In the present study, we addressed the role of c-Maf in asthma by studying transgenic (Tg) mice overexpressing c-Maf in CD4 + T cells under the control of the CD2 promoter. As shown, lung CD4 + T cells of c-maf-Tg mice produced more IL-5 at the early stage (day 2) of culture in the presence of IL-4 than wild-type control cells. Consistently, c-maf-Tg mice spontaneously showed increased IL-5 expression and eosinophils in the bronchial alveolar lavage fluid (BALF) and activated IL-5 signal transduction via Raf-1 and Ras in lung eosinophils. Finally, IL-13 was suppressed in the BALF of c-maf-Tg mice and in supernatants of Tg lung CD4 + T cells cultured in the presence of IL-2. Consistently, retroviral overexpression of c-Maf suppressed IL-13 production in developing lung Th2 cells. In summary, c-Maf induces IL-5 production in lung CD4 + T cells at an early stage, but along with IL-2 suppresses IL-13 production in differentiating lung Th2 cells, thereby explaining the finding that overexpression of c-Maf does not cause airway hyperresponsiveness, a hallmark feature of asthma.

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“…Serum levels of total IgE, OVA-specific IgE, IgG1, and IgG2a were measured by ELISA as previously described (29). The anti-OVA Ab titers of samples were related to internal pooled standards that were generated in the laboratory and expressed as ELISA units.…”

Section: Measurement Of Total and Ova-specific Absmentioning

confidence: 99%

“…Cytokine levels in the BAL fluid and cell culture supernatants were measured by ELISA as previously described (29). IFN-␥, IL-4, IL-5, IL-10, IL-12 (BD PharMingen, San Diego, CA), and IL-13 (R&D Systems, Minneapolis, MN) ELISAs were performed according to the manufacturer's directions.…”

Section: Measurement Of Cytokinesmentioning

confidence: 99%

Contribution of Antigen-Primed CD8+ T Cells to the Development of Airway Hyperresponsiveness and Inflammation Is Associated with IL-13

Miyahara

Takeda

Kodama

et al. 2004

The Journal of Immunology

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102

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The role of Th2/CD4 T cells, which secrete IL-4, IL-5, and IL-13, in allergic disease is well established; however, the role of CD8+ T cells (allergen-induced airway hyperresponsiveness (AHR) and inflammation) is less clear. This study was conducted to define the role of Ag-primed CD8+ T cells in the development of these allergen-induced responses. CD8-deficient (CD8−/−) mice and wild-type mice were sensitized to OVA by i.p. injection and then challenged with OVA via the airways. Compared with wild-type mice, CD8−/− mice developed significantly lower airway responsiveness to inhaled methacholine and lung eosinophilia, and exhibited decreased IL-13 production both in vivo, in the bronchoalveolar lavage (BAL) fluid, and in vitro, following Ag stimulation of peribronchial lymph node (PBLN) cells in culture. Reconstitution of sensitized and challenged CD8−/− mice with allergen-sensitized CD8+ T cells fully restored the development of AHR, BAL eosinophilia, and IL-13 levels in BAL and in culture supernatants from PBLN cells. In contrast, transfer of naive CD8+ T cells or allergen-sensitized CD8+ T cells from IL-13-deficient donor mice failed to do so. Intracellular cytokine staining of lung as well as PBLN T cells revealed that CD8+ T cells were a source of IL-13. These data suggest that Ag-primed CD8+ T cells are required for the full development of AHR and airway inflammation, which appears to be associated with IL-13 production from these primed T cells.

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The Role of IL-13 in Established Allergic Airway Disease

Cited by 169 publications

References 44 publications

Human interferon lambda-1 (IFN-λ1/IL-29) modulates the Th1/Th2 response

Human interferon lambda-1 (IFN-λ1/IL-29) modulates the Th1/Th2 response

A stage‐specific functional role of the leucine zipper transcription factor c‐Maf in lung Th2 cell differentiation

Contribution of Antigen-Primed CD8+ T Cells to the Development of Airway Hyperresponsiveness and Inflammation Is Associated with IL-13

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