Inhibition of signal transducer and activator of transcription 1 attenuates allergen-induced airway inflammation and hyperreactivity

Quarcoo, David; Weixler, Silke; Groneberg, David A.; Joachim, Ricarda; Ahrens, Birgit; Wagner, Andreas H.; Hecker, Markus; Hamelmann, Eckard

doi:10.1016/j.jaci.2004.03.055

Cited by 74 publications

(54 citation statements)

References 49 publications

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“…On days 28 and 29, mice were challenged intranasally with 50 g OVA. Airway responsiveness was measured via whole-body plethysmography on day 31 in unrestrained mice after challenge with increasing doses of metacholine (MCh, Sigma-Aldrich) as described elsewhere (20). Recombinant A. viteae cystatin (20 g) or the same amount of control protein (both proteins applied without adjuvant) in PBS was injected i.p.…”

Section: Murine Asthma Model and Measurement Of Airway Hyperreactivitmentioning

confidence: 99%

A Helminth Immunomodulator Reduces Allergic and Inflammatory Responses by Induction of IL-10-Producing Macrophages

Schnoeller

Rausch

Pillai

et al. 2008

The Journal of Immunology

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226

196

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The coincidence between infections with parasitic worms and the reduced prevalence of allergic disease in humans and in animal models has prompted the search for helminth molecules with antiallergic and antiinflammatory potential. We report herein that filarial cystatin, a secreted protease inhibitor of filarial nematodes, suppresses Th2-related inflammation and the ensuing asthmatic disease in a murine model of OVA-induced allergic airway responsiveness. Treatment with recombinant filarial cystatin inhibited eosinophil recruitment, reduced levels of OVA-specific and total IgE, down-regulated IL-4 production, and suppressed allergic airway hyperreactivity when applied during or after sensitization and before challenge with the allergen. Depletion of macrophages by clodronate-containing liposomes prevented the curative effects and restored the levels of infiltrating cells, IgE, and allergic airway reactivity. Blocking of IL-10 by application of anti-IL-10 receptor Abs restored the reduced number of infiltrating cells and the levels of OVA-specific IgE. In contrast, depletion of regulatory T cells by anti-CD25 Abs had only limited effects. Cystatin also modulated macrophage-mediated inflammation in a murine model of dextran sulfate sodium-induced colitis, leading to reduction of inflammatory infiltrations and epithelial damage. Our data demonstrate that treatment with a single helminth protein can exert the antiallergic effects of helminth infections.

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Section: Murine Asthma Model and Measurement Of Airway Hyperreactivitmentioning

confidence: 99%

A Helminth Immunomodulator Reduces Allergic and Inflammatory Responses by Induction of IL-10-Producing Macrophages

Schnoeller

Rausch

Pillai

et al. 2008

The Journal of Immunology

Self Cite

226

196

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“…Stat1 has been implicated in the negative regulation of Th2 cytokine signaling (11)(12)(13). Therefore, we hypothesized that Stat1 may play a role in IL-13-induced PDGF expression.…”

Section: Stat1-signaling Suppresses Il-13-stimulated Pdgf Expressionmentioning

confidence: 99%

“…Thus, Stat6 is required for many aspects of IL-13-induced airway remodeling. Stat1 is also activated by IL-13 in a variety of lung cell types (10) and yet negatively regulates IL-13-induced signaling in pulmonary cell types (11)(12)(13). We recently demonstrated that Stat1-deficient (Stat1 Ϫ/Ϫ ) mice exhibited more severe pulmonary fibrosis after bleomycin injury compared with wild-type Stat1 ϩ/ϩ mice (14).…”

mentioning

confidence: 99%

Opposing Actions of Stat1 and Stat6 on IL-13-Induced Up-Regulation of Early Growth Response-1 and Platelet-Derived Growth Factor Ligands in Pulmonary Fibroblasts

Ingram

Antao-Menezes

Mangum

et al. 2006

The Journal of Immunology

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IL-13 is a key cytokine involved in airway remodeling in asthma. We previously reported that IL-13 stimulated the mitogenesis of lung fibroblasts via platelet-derived growth factor (PDGF)-AA. In this report, we show that IL-13 increases PDGF-A and PDGF-C mRNA levels through a dual intracellular cascade that requires coactivation of Stat6 and Stat1 to impact transcriptional regulation of the early growth response (Egr)-1 gene, which then drives PDGF expression. Increased levels of PDGF-AA and PDGF-CC protein were observed in vivo in the airways of IL-13 transgenic mice. IL-13 up-regulated PDGF-A and PDGF-C mRNA levels in lung fibroblasts isolated from three different background strains of mice. However, IL-13-induced PDGF-A and PDGF-C mRNA levels were significantly reduced in Stat6-deficient (Stat6−/−) fibroblasts as compared with wild-type Stat6+/+ fibroblasts. In contrast, IL-13-induced PDGF-A and PDGF-C mRNAs were enhanced in Stat1−/− fibroblasts as compared with Stat1+/+ fibroblasts. IL-13 did not up-regulate PDGF-A or PDGF-C mRNA levels in Egr-1−/− fibroblasts. Moreover, IL-13 did not increase Egr-1 mRNA and protein levels in Stat6−/− fibroblasts and yet enhanced Egr-1 mRNA and protein levels in Stat1−/− fibroblasts. Our findings support the hypothesis that Stat6 and Stat1 exert stimulatory and inhibitory effects on Egr-1 and PDGF ligand mRNA transcription, respectively. This novel mechanism could aid in identifying molecular targets for the treatment of chronic airway remodeling and fibrosis in asthma.

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“…In vivo and in vitro experiments showed that the up-regulation of both CD40 and VCAM-1 expression by STAT-1 is effectively reduced using decoy ODNs directed against this transcription factor (Wagner et al, 2002;Quarcoo et al, 2004).…”

Section: An Important Cytokine That Is Produced By Activated T-helpermentioning

confidence: 99%

Pre-Transplant Therapy in Experimental Heart Transplantation

Stojanović¹,

Wagner²,

Schöndube³

et al. 2012

Cardiac Transplantation

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Inhibition of signal transducer and activator of transcription 1 attenuates allergen-induced airway inflammation and hyperreactivity

Cited by 74 publications

References 49 publications

A Helminth Immunomodulator Reduces Allergic and Inflammatory Responses by Induction of IL-10-Producing Macrophages

A Helminth Immunomodulator Reduces Allergic and Inflammatory Responses by Induction of IL-10-Producing Macrophages

Opposing Actions of Stat1 and Stat6 on IL-13-Induced Up-Regulation of Early Growth Response-1 and Platelet-Derived Growth Factor Ligands in Pulmonary Fibroblasts

Pre-Transplant Therapy in Experimental Heart Transplantation

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