Th2 cytokines and asthma — Interleukin-9 as a therapeutic target for asthma

Zhou, Yuhong; McLane, Michael; Levitt, Roy C.

doi:10.1186/rr42

Cited by 73 publications

(10 citation statements)

References 51 publications

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“…Additionally, IL-9 was termed a candidate gene for asthma since it was found by linkage analyses to reside within a cytokine gene cluster together with IL-3, IL-4, and IL-5 on human chromosome 5 (8). In line with these findings, IL-9 as a pleiotropic cytokine, has several activities that favor the development of allergic asthma (9, 10). IL-9 enhances the IL-4-mediated production of IgE in human and murine B cells (11), promotes eosinophil maturation in synergy with IL-5 (12), and stimulates mucin transcription in respiratory epithelial cells (13).…”

Section: Introductionsupporting

confidence: 52%

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The Tick Salivary Protein Sialostatin L Inhibits the Th9-Derived Production of the Asthma-Promoting Cytokine IL-9 and Is Effective in the Prevention of Experimental Asthma

Horká

Staudt

Klein

et al. 2012

The Journal of Immunology

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Ticks developed a multitude of different immune evasion strategies in order to obtain a blood meal. Sialostatin L is an immunosuppressive cysteine protease inhibitor present in the saliva of the hard tick Ixodes scapularis. Herein we demonstrate that sialostatin L strongly inhibits the production of IL-9 by Th9 cells. Since we could show recently that Th9-derived IL-9 is essentially involved in the induction of asthma symptoms, sialostatin L was used for the treatment of experimental asthma. Application of sialostatin L in a model of experimental asthma almost completely abrogated airway hyperresponsiveness and eosinophilia. Our data suggest that sialostatin L can prevent experimental asthma, most likely by inhibiting the IL-9 production of Th9 cells. Thus, alternative to IL-9 neutralization sialostatin L provides the basis for the development of innovative therapeutic strategies to treat asthma.

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Section: Introductionsupporting

confidence: 52%

“…IL-9 was initially thought to be preferentially produced by Th2 cells and subsequently it has been shown that IL-9 induced asthmatic symptoms similar to those induced by IL-4 (9, 10). This asthma-promoting potency of IL-9 was found to be at least partially mediated by IL-13 that was produced from airway epithelial cells (36).…”

Section: Discussionmentioning

confidence: 99%

The Tick Salivary Protein Sialostatin L Inhibits the Th9-Derived Production of the Asthma-Promoting Cytokine IL-9 and Is Effective in the Prevention of Experimental Asthma

Horká

Staudt

Klein

et al. 2012

The Journal of Immunology

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“…Transgene expression of IL-9 in the lungs of mice resulted in lymphocytic and eosinophilic infiltration of the lung, airway epithelial hypertrophy with mucus production, mast cell hyperplasia and production of IL-4, IL-5 and IL-13 [53]. Blocking humanized antibodies to IL-9 are currently in development [54]. However, these may also prove to be disappointing, as the overall current evidence does seem to suggest that targeting single T cell cytokines would not be an effective therapeutic approach for asthma.…”

Section: Eosinophil Accumulation -Il-4 and Il-13mentioning

confidence: 98%

Control of Eosinophil Toxicity in the Lung

Walsh¹,

Al-Rabia²,

Blaylock³

et al. 2005

CDTIA

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The inappropriate accumulation of eosinophils and the subsequent release of their potent pro-inflammatory mediator arsenal are thought to be important contributors to the pathogenesis of asthma and other allergic diseases. It is also becoming apparent that eosinophils may play a role in the orchestration of immune responses in the asthmatic lung. There is therefore much interest in the development of strategies to limit or prevent eosinophil-induced toxicity. The mechanisms by which eosinophils accumulate in the peribronchial tissues of the lung are complex and include enhanced differentiation and release from the bone marrow, selective adhesion and transendothelial migration, directed movement in response to specific chemotactic mediators and finally prolonged survival as a consequence of delayed apoptosis. Thus it can be appreciated that there are many points at which the toxicity of eosinophils can be limited or even prevented. Important areas for potential advances in glucocorticoid (GC) development include efforts to dissociate their anti-inflammatory effects from unwanted side effects. Other areas include the development of humanized monoclonal antibodies against IL-4, IL-13 and IL-5 together with the inhibition of adhesion pathways and/or chemokines responsible for eosinophil accumulation in the asthmatic lung. Several avenues of research are currently underway in an attempt to define mechanisms by which pro-inflammatory cells such as eosinophils can be safely removed from the asthmatic lung through apoptosis induction and their subsequent ingestion by phagocytes. This review will discuss both the potential and shortcomings of these diverse approaches to limit eosinophil toxicity in the asthmatic lung.

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“…Transgene expression of IL-9 in the lungs of mice resulted in lymphocytic and eosinophilic infiltration of the lung, airway epithelial hypertrophy with mucus production, mast cell hyperplasia and production of IL-4, IL-5 and IL-13 [45]. Blocking humanised antibodies to IL-9 are currently in development [46]. TNF-α is expressed in asthmatic airways and levels are elevated in induced sputum from patients with COPD [47].…”

Section: Pro-inflammatory Cytokinesmentioning

confidence: 99%

Targeting Airway Inflammation: Novel Therapies for the Treatment of Asthma

Walsh

2006

CMC

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It is now widely accepted that airway inflammation is the key factor underlying the pathogenesis of asthma. Inhaled corticosteroids remain the most important anti-inflammatory treatment for asthma. However, they are rather non-specific in their actions and their use raises concerns over side effects and compliance issues, particularly in children and adolescents. Moreover, a significant sub-group of asthmatic patients responds poorly or not at all to high-dose inhaled or systemic steroid treatment. Therefore, much effort is being made to develop novel more specific and safer therapy for asthma. Significant areas of drug development include humanised monoclonal antibodies (mAb) for asthma therapy including those against IL-4, IL-5, TNF and IL-13. Asthma-relevant cytokines or chemokines have been targeted in a number of other ways. These include: (1) the use of humanised blocking mAb to their receptors; (2) removal of cytokines or chemokines via binding to soluble receptors or small molecule receptor antagonists; and (3) drugs that block the signal transduction pathways activated following the interaction of cytokines or chemokines with their receptors. Another approach is to use anti-inflammatory cytokines directly or encourage their production thereby suppressing the allergic inflammatory process; these chemokines include IL-10, IL-12 and IFN-gamma. Finally, a further promising area involves targeting the allergic portion of the asthma phenotype using humanised anti-IgE mAb. This review will discuss the current status, therapeutic potential and potential problems of these novel drug developments in asthma therapy.

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Th2 cytokines and asthma — Interleukin-9 as a therapeutic target for asthma

Cited by 73 publications

References 51 publications

The Tick Salivary Protein Sialostatin L Inhibits the Th9-Derived Production of the Asthma-Promoting Cytokine IL-9 and Is Effective in the Prevention of Experimental Asthma

The Tick Salivary Protein Sialostatin L Inhibits the Th9-Derived Production of the Asthma-Promoting Cytokine IL-9 and Is Effective in the Prevention of Experimental Asthma

Control of Eosinophil Toxicity in the Lung

Targeting Airway Inflammation: Novel Therapies for the Treatment of Asthma

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