Requirement for IL-13 Independently of IL-4 in Experimental Asthma

Grünig, Gabriele; Warnock, Martha L.; Wakil, Adil E.; Venkayya, Rajeev; Brombacher, Frank; Rennick, Donna; Sheppard, Dean; Mohrs, Markus; Donaldson, Debra D.; Locksley, Richard M.; Corry, David B.

doi:10.1126/science.282.5397.2261

Cited by 1,767 publications

(1,534 citation statements)

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“…Since previous studies have shown that PD-L2 expression may be regulated in some cell types by Th2 cytokines or Th2 cells [21], and because asthma is believed to be a Th2-driven disease [23][24][25][26][27][28][29][30][31][32], it was of interest to examine whether PD-L2 can play a role in immune regulation in this context.…”

Section: Discussionmentioning

confidence: 99%

“…Asthma is a chronic disease which can be characterized by airway hyper-responsiveness, mucus hypersecretion by goblet cells, infiltration of the airway wall with leukocytes, and elevation of serum IgE [23 24]. Studies in mouse models have established a critical role for Th2 cells, DC, Treg [24][25][26][27][28], and the Th2 type cytokines IL-4, IL-5, IL-9, and IL-13 in the asthmatic response [23,26,[29][30][31][32]. The role of the PD-1/PD-L1/PD-L2 axis in asthma is currently unknown.…”

Section: Introductionmentioning

confidence: 99%

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Paradoxical role of programmed death‐1 ligand 2 in Th2 immune responses in vitro and in a mouse asthma model in vivo

et al. 2004

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Programmed death-1 ligand 2 (PD-L2) is a ligand for programmed death-1 (PD-1), a receptor that plays an inhibitory role in T cell activation. Since previous studies have shown upregulation of PD-L2 expression by Th2 cytokines, and asthma is driven by a Th2 response, we hypothesized that PD-L2 might be involved in regulation of the immune response in this disease. We have found that lungs from asthmatic mice had sustained up-regulation of PD-1 and PD-L2, with PD-L2 primarily on dendritic cells. Although addition of PD-L2-Fc in vitro led to decreased T cell proliferation and cytokine production, administration of PD-L2-Fc in vivo in a mouse asthma model resulted in elevated serum IgE levels, increased eosinophilic and lymphocytic infiltration into bronchoalveolar lavage fluid, higher number of cells in the draining lymph nodes, and production of IL-5 and IL-13 from these cells. Although PD-1 was expressed on regulatory T cells, PD-L2-Fc did not affect regulatory T cell activity in vitro. This study provides in vivo evidence of an exacerbated inflammatory response following PD-L2-Fc administration and indicates a potential role for this molecule in Th2-mediated diseases such as asthma.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Paradoxical role of programmed death‐1 ligand 2 in Th2 immune responses in vitro and in a mouse asthma model in vivo

et al. 2004

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“…IL-13, a Th2-type cytokine, is a central mediator for allergic inflammation [8,9]. The blockade of IL-13 markedly inhibits allergen-induced airway hyperresponsiveness, mucus production, and eosinophilia whereas IL-13 delivery to the airway causes these effects in mice [8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

“…these effects in mice [8][9][10][11]. Therefore, IL-13 as well as TSLP is necessary and sufficient for the development of allergic inflammation.…”

mentioning

confidence: 99%

“…Endogenous stimulators of TSLP production might be released upon the cellular damage associated with the tissue isolation and contribute to the basal TSLP production. This issue is presently under investigation.IL-13 plays a central role in the development of airway inflammation in asthma and allergic rhinitis [8][9][10][11][22][23][24]. Recent studies suggested that TSLP functions upstream of IL-13 in the skin and lung allergic inflammation [12,13].…”

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Thymic stromal lymphopoietin is a critical mediator of IL‐13‐driven allergic inflammation

et al. 2009

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Both thymic stromal lymphopoietin (TSLP) and IL-13 are essential cytokines for the development of allergic inflammation. However, a causal link between TSLP and IL- 13 has not yet been fully elucidated. This study aimed to investigate whether IL-13 induces TSLP expression and whether the induction contributes to the development of allergic inflammation. We found that IL-13 induced TSLP expression in mouse nasal tissue specimens in a Stat6-dependent manner. In addition, intranasal challenge of mice with IL-13 induced TSLP expression in the nasal epithelium. Importantly, intranasal IL-13 challenge induced eosinophilia and goblet cell hyperplasia in the nasal mucosa in mice, which was inhibited by the blockade of TSLP activity with anti-TSLP Ab. These findings suggest that TSLP is an important mediator of IL-13-driven allergic inflammation in the nasal mucosa. Taken together with the recent findings that IL-13 is a critical downstream element for TSLP-driven allergic inflammation, TSLP may function both upstream and downstream of IL-13, thus providing an additional rationale as to why TSLP plays such a central role in the development of allergic inflammation.Key words: Allergic inflammation . Epithelial cells . IL-13 . Thymic stromal lymphopoietin Supporting Information available online IntroductionThymic stromal lymphopoietin (TSLP) is an IL-7-like cytokine, which binds to a TSLP receptor (TSLPR) consisting of the IL-7 receptor a-chain and a common g receptor-like chain [1,2]. TSLP was originally identified as a factor derived from a thymic stromal cell line that could support the growth of a mouse B-cell line [3].However, recent evidence has demonstrated TSLP, derived from epithelial cells, to be a critical factor for allergic inflammation [1,2,4]. For instance, transgenic mice expressing TSLP in keratinocytes or in lung epithelial cells develop atopic dermatitisor asthma-like inflammation in the skin or the lung, respectively, while TSLPR-deficient mice fail to develop an inflammatory lung response to inhaled antigen [5][6][7].IL-13, a Th2-type cytokine, is a central mediator for allergic inflammation [8,9]. The blockade of IL-13 markedly inhibits allergen-induced airway hyperresponsiveness, mucus production, and eosinophilia whereas IL-13 delivery to the airway causes SHORT COMMUNICATION 3078these effects in mice [8][9][10][11]. Therefore, IL-13 as well as TSLP is necessary and sufficient for the development of allergic inflammation. However, the relationship between TSLP and IL-13 in allergic inflammation has not yet been fully elucidated.This study thus investigated the causal link between IL-13 and TSLP in allergic inflammation. For this purpose, we examined the effects of IL-13 on TSLP expression both in vitro and in vivo using mouse nasal tissue explants and a mouse model of allergic inflammation in the nasal mucosa, respectively. The current results suggest that TSLP is induced by IL-13 and is critical for the development of IL-13-driven allergic inflammation. Because recent studies suggest that TSLP-dri...

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Characterization in mice of the immunological properties of five allergenic acid anhydrides

Dearman

Warbrick

Humphreys

et al. 2000

J of Applied Toxicology

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Occupational exposure to certain acid anhydrides, including trimellitic anhydride (TMA), maleic anhydride (MA), phthalic anhydride (PA), hexahydrophthalic anhydride (HHPA) and methyltetrahydrophthalic anhydride (MTHPA), has been associated with the development of respiratory allergy or asthma. There is considerable debate about the mechanisms through which such chemicals may cause respiratory sensitization, particularly concerning a universal requirement for specific IgE antibody. Despite the controversy regarding an obligatory role for IgE, there is a growing consensus that chemical respiratory hypersensitivity is associated with the selective development of T lymphocytes with a type 2 (Th2) phenotype. In the current investigations we have characterized in mice the nature of immune responses provoked by prolonged topical exposure to five acid anhydrides. Under application conditions where similar overall immunogenicity was achieved, we have compared cytokine responses induced by PA, MA, HHPA and MTHPA with those provoked by concurrent exposure to TMA or to the reference contact allergen 2, 4-dinitrochlorobenzene (DNCB). Lymph node cells (LNC) draining the site of topical exposure to DNCB invariably expressed high levels of the type 1 cytokines interferon-gamma (IFN-gamma) and interleukin-12 (IL-12), but only low levels of the type 2 cytokines interleukin-4 (IL-4) and interleukin-10 (IL-10). In each experiment, TMA-activated LNC displayed the converse, type 2, phenotype of cytokine production. The other acid anhydrides in each case provoked a type 2 cytokine secretion profile, with comparable IL-10 expression but somewhat less vigorous IL-4 production compared with that observed following exposure to the reference respiratory allergen TMA. In every experiment relatively low levels of IFN-gamma and IL-12 were elaborated by acid anhydride-activated LNC, with the exception of PA-stimulated LNC that displayed increased amounts of IL-12 in comparison with other acid anhydrides. Thus, prolonged topical exposure of mice to five different acid anhydrides in each case resulted in the development of a predominantly Th2-type cytokine secretion phenotype, consistent with the ability of these materials to provoke asthma and respiratory allergy through a type 2 (possibly IgE-mediated) mechanism. Taken together with the results of previous investigations with a wider range of chemical allergens, these data suggest that induced cytokine secretion patterns or 'fingerprints' allow discrimination between contact and respiratory allergens and consequently represent a suitable approach to prospective evaluation of respiratory sensitization hazard.

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Requirement for IL-13 Independently of IL-4 in Experimental Asthma

Cited by 1,767 publications

References 33 publications

Paradoxical role of programmed death‐1 ligand 2 in Th2 immune responses in vitro and in a mouse asthma model in vivo

Paradoxical role of programmed death‐1 ligand 2 in Th2 immune responses in vitro and in a mouse asthma model in vivo

Thymic stromal lymphopoietin is a critical mediator of IL‐13‐driven allergic inflammation

Characterization in mice of the immunological properties of five allergenic acid anhydrides

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