Niflumic Acid Suppresses Interleukin-13–induced Asthma Phenotypes

Nakano, Takako; Inoue, Hiromasa; Fukuyama, Satoru; Matsumoto, Koichiro; Matsumura, Manabu; Tsuda, Miyuki; Matsumoto, Takafumi; Aizawa, Hisamichi; Nakanishi, Yoichi

doi:10.1164/rccm.200410-1420oc

Cited by 77 publications

(76 citation statements)

References 53 publications

(66 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because chloride transport regulates mucus production (11), anion transporters are suggested to be involved in mucus hypersecretion in bronchial asthma. Consistent with this idea, niflumic acid, a broad inhibitor of anion transport, suppresses the development of asthma in mice (12). Previous reports showed that Th2-type cytokines including IL-13 induce expression of gob-5 (mCLCA3), which had been thought to be a chloride transporter, suggesting a critical role for gob-5 in mucus overproduction in bronchial asthma (13,14).…”

mentioning

confidence: 78%

Identification of Pendrin as a Common Mediator for Mucus Production in Bronchial Asthma and Chronic Obstructive Pulmonary Disease

Nakao¹,

Kanaji²,

Ohta³

et al. 2008

The Journal of Immunology

Self Cite

118

148

View full text Add to dashboard Cite

Excessive production of airway mucus is a cardinal feature of bronchial asthma and chronic obstructive pulmonary disease (COPD) and contributes to morbidity and mortality in these diseases. IL-13, a Th2-type cytokine, is a central mediator in the pathogenesis of bronchial asthma, including mucus overproduction. Using a genome-wide search for genes induced in airway epithelial cells in response to IL-13, we identified pendrin encoded by the SLC26A4 (PDS) gene as a molecule responsible for airway mucus production. In both asthma and COPD mouse models, pendrin was up-regulated at the apical side of airway epithelial cells in association with mucus overproduction. Pendrin induced expression of MUC5AC, a major product of mucus in asthma and COPD, in airway epithelial cells. Finally, the enforced expression of pendrin in airway epithelial cells in vivo, using a Sendai virus vector, rapidly induced mucus overproduction in the lumens of the lungs together with neutrophilic infiltration in mice. These findings collectively suggest that pendrin can induce mucus production in airway epithelial cells and may be a therapeutic target candidate for bronchial asthma and COPD.

show abstract

mentioning

confidence: 78%

Identification of Pendrin as a Common Mediator for Mucus Production in Bronchial Asthma and Chronic Obstructive Pulmonary Disease

Nakao¹,

Kanaji²,

Ohta³

et al. 2008

The Journal of Immunology

Self Cite

118

148

View full text Add to dashboard Cite

show abstract

“…Chloride channel blockers, such as niflumic acid (NFA) and its derivatives, reduce mucin secretion and improve airway function in asthma models (28)(29)(30)(31)(32)(33)(34)(35)(36); however, further drug development has been hampered by several factors, including a lack of knowledge about the molecular identity of CaCC (37)(38)(39). Our findings that TMEM16A-CaCC is up-regulated in the airway epithelium of asthmatics and preferentially in secretory cells in several asthma models support the relevance of this molecule as a target for the treatment of this disease.…”

Section: Tmem16a Is Preferentially Expressed In Secretory Cells In Asmentioning

confidence: 99%

Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction

Huang

Zhang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

295

342

View full text Add to dashboard Cite

Mucous cell hyperplasia and airway smooth muscle (ASM) hyperresponsiveness are hallmark features of inflammatory airway diseases, including asthma. Here, we show that the recently identified calciumactivated chloride channel (CaCC) TMEM16A is expressed in the adult airway surface epithelium and ASM. The epithelial expression is increased in asthmatics, particularly in secretory cells. Based on this and the proposed functions of CaCC, we hypothesized that TMEM16A inhibitors would negatively regulate both epithelial mucin secretion and ASM contraction. We used a high-throughput screen to identify small-molecule blockers of TMEM16A-CaCC channels. We show that inhibition of TMEM16A-CaCC significantly impairs mucus secretion in primary human airway surface epithelial cells. Furthermore, inhibition of TMEM16A-CaCC significantly reduces mouse and human ASM contraction in response to cholinergic agonists. TMEM16A-CaCC blockers, including those identified here, may positively impact multiple causes of asthma symptoms.A sthma is a significant cause of morbidity and mortality worldwide, and the prevalence of this disease is increasing among all age, sex, and racial groups. Characteristic features of asthma include inflammation, subepithelial fibrosis, hyperplasia of mucus-producing cells, accumulation of mucus within airway lumens, hyperplasia of airway smooth muscle (ASM), and ASM hyperresponsiveness. Together, these symptoms impair lung function by limiting the flow of gases to and from the alveoli in the distal lung.The current standard of care for asthma involves inhaled corticosteroids for the management of inflammation combined with long-acting agonists of β2-adrenergic receptors. Despite this treatment, lung function is not improved in 30-45% of asthmatic patients, and exacerbations continue to be a major problem (reviewed in ref. 1). Asthma can be divided into at least two distinct molecular phenotypes defined by the degree of Th2 inflammation (2, 3). Cytokines, including IL-4 and IL-13, promote airway epithelial mucous cell metaplasia, subepithelial fibrosis, and hyperplasia of smooth muscle in Th2-high asthmatics, and these patients generally show improved lung function with inhaled corticosteroid therapy. A greater understanding of this heterogeneity and the molecular and physiological events that lead to airway remodeling might lead to improved diagnosis and treatment.Calcium-activated chloride channels (CaCCs) have been ascribed numerous cellular functions (reviewed in refs. 4 and 5), among these are epithelial fluid secretion and smooth muscle contraction, both of which contribute to the progression and severity of asthma. Moreover, calcium-activated chloride currents in the airway epithelium are enhanced by the Th2 cytokines IL-4 and IL-13, as well as IFN-γ (6). For these reasons, CaCC is an attractive potential therapeutic target for asthma (7). However, the study of CaCC was impeded by lack of information about the gene(s) encoding this channel. It was only relatively recently that TMEM16A (transmembrane p...

show abstract

“…Like other members of STAT family of proteins, STAT6 has a dual role as a signaling molecule and as a transcription factor. IL-13 is purported to use the STAT6 signaling pathway to mediate its tissue inflammatory and structural effects (Nakano et al, 2006). This widely held belief is the result of the well-documented ability of IL-13 to activate STAT6 in a variety of tissues (Hebenstreit et al, 2006;Nakano et al, 2006;Palmqvist et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…IL-13 is purported to use the STAT6 signaling pathway to mediate its tissue inflammatory and structural effects (Nakano et al, 2006). This widely held belief is the result of the well-documented ability of IL-13 to activate STAT6 in a variety of tissues (Hebenstreit et al, 2006;Nakano et al, 2006;Palmqvist et al, 2006). Western blot analysis demonstrates that the binding of IL-13 to its receptor on the surface of HEL cells or Dami cells activates STAT6.…”

Section: Discussionmentioning

confidence: 99%

IL‐13 upregulates GPIIb expression in megakaryocytic cell lines via STAT6

Shi

Cai

Zhou

et al. 2010

The Anatomical Record

View full text Add to dashboard Cite

Interleukin 13 (IL-13) is a key cytokine involved in the regulation of inflammatory, immune responses, and cell differentiation. The present study was to investigate the effect of IL-13 on the expression of glycoprotein IIb (GPIIb), a megakaryocytic gene, in Dami cells (human megakaryoblastic leukemia cell line) and HEL cells (human erythroleukemic cell line, which has both erythroid and megakaryocytic markers). Furthermore, it addresses the mechanisms governing the regulation of GPIIb expression by IL-13. The molecular responses of Dami cells and HEL cells to IL-13 treatment were analyzed by RT-PCR, Western blot, chromatin immunoprecipitation (ChIP) and flow cytometry analysis. We show that IL-13Ra1 and IL-4Ra are expressed in Dami cells and HEL cells. The expression of GPIIb was significantly upregulated at the mRNA and protein levels by treatment with IL-13. Moreover, IL-13 induced phosphorylation of signal transducer and activator of transcription 6(STAT6). By using a STAT6-specific antibody and PCR primers designed to yield a product, which encompasses the STAT6 binding site of the GPIIb promoter, we have shown the binding of the IL-13-mediated activation of STAT6 to the promoter of GPIIb gene. These results broaden the involvement of IL-13 into megakaryocyte differentiation by STAT6 pathway.

show abstract

Niflumic Acid Suppresses Interleukin-13–induced Asthma Phenotypes

Abstract: These findings suggest that a chloride channel inhibitor can control IL-13-mediated airway features at least by suppressing JAK/STAT6 activation.

Cited by 77 publications

References 53 publications

Identification of Pendrin as a Common Mediator for Mucus Production in Bronchial Asthma and Chronic Obstructive Pulmonary Disease

Identification of Pendrin as a Common Mediator for Mucus Production in Bronchial Asthma and Chronic Obstructive Pulmonary Disease

Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction

IL‐13 upregulates GPIIb expression in megakaryocytic cell lines via STAT6

Contact Info

Product

Resources

About