Small Interfering RNA against Transcription Factor STAT6 Inhibits Allergic Airway Inflammation and Hyperreactivity in Mice

Darcan-Nicolaisen, Yasemin; Meinicke, Holger; Fels, Gabriele; Hegend, Olga; Haberland, Annekathrin; Kühl, Anja A.; Loddenkemper, Christoph; Witzenrath, Martin; Kube, SM; Henke, Wolfgang; Hamelmann, Eckard

doi:10.4049/jimmunol.0713433

Cited by 66 publications

(52 citation statements)

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“…Also, a number of studies have reported that RNAi can be used in DCs to diagnose and treat bronchial asthma (36)(37)(38)(39). Darcan-Nicolaisen et al (40) discovered that the two major signs of allergic asthma in the OVA-induced asthma mouse model, which are airway inflammation and hyperactivity, were significantly ameliorated by signal transducer and activator of transcription 6 (STAT6) silencing in airway epithelial cells using the administration of siRNA nose drops. Moriwaki et al (41) demonstrated that siRNA-mediated suppressor of cytokine signaling 3 (SOCS3) gene silencing could suppress the airway reactivity and eosinophilic infiltration that was induced by allergenic stimulation in asthmatic mice.…”

Section: Discussionmentioning

confidence: 99%

CD80 and CD86 knockdown in dendritic cells regulates Th1/Th2 cytokine production in asthmatic mice

Yan

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Dendritic cells (DCs) are associated with the activation and differentiation of T helper (Th) cells. Cluster of differentiation (CD)80 and CD86, the co-stimulatory molecules highly expressed in DCs, have are prominent in promoting the differentiation of Th cells toward Th2 cells. However, little is known about the effect of CD80 and CD86 knockdown on Th1/Th2 cytokine production in mature DCs (mDCs). The aim of the present study was to investigate whether small-interfering RNA (siRNA) could suppress the surface expression of CD80 and CD86 in mDCs. The effects of CD80 and CD86 knockdown in mDCs on Th1/Th2 cytokine expression were examined using an asthmatic murine model. DCs were isolated, separated and cultured in vitro. Flow cytometry was used to examine the expression of CD11c, CD80 and CD86 on the DCs. The DCs were transfected with CD80-and CD86-specific siRNA, while non-siRNA and negative siRNA controls were also designed. Then, the mRNA and protein expression levels of CD80 and CD86 were determined by reverse transcription-quantitative polymerase chain reaction and flow cytometry, respectively. The levels of interferon (IFN)-γ and interleukin (IL)-4 produced by T cells co-cultured with mDCs were measured by enzyme-linked immunosorbent assay. Substantial downregulation of CD80 and CD86 mRNA and protein levels were observed in the mDCs following transfection with siRNA. The level of IFN-γ produced by T cells co-cultured with mDCs was significantly increased in the siRNA group, while IL-4 production was significantly decreased. These results show that specific targeting of CD80 and CD86 with siRNA is able to suppress CD80/CD86 expression and consequently regulate Th1/Th2 cytokine levels by increasing IFN-γ production and decreasing IL-4 levels in an asthmatic murine model.

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Section: Discussionmentioning

confidence: 99%

CD80 and CD86 knockdown in dendritic cells regulates Th1/Th2 cytokine production in asthmatic mice

Yan

et al. 2016

Experimental and Therapeutic Medicine

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“…29) In mouse models of allergic bronchial asthma, development of AHR was inhibited by STAT6 gene knockout 16,17) and by the treatment with a STAT6 inhibitory peptide 18) or a short interfering RNA against STAT6. 30) In addition to the phosphorylation of STAT6, a significant increase in the level of phosphorylated STAT1 was also found in BSMs of the antigen-challenged mice (Fig. 2).…”

Section: Discussionmentioning

confidence: 78%

Phosphorylation of Signal Transducer and Activator of Transcription 6 (STAT6) and STAT1, but Not STAT3, Induced by Antigen Inhalation in Bronchial Smooth Muscles of Sensitized Mice

Chiba

Todoroki

Misawa

2010

Biological & Pharmaceutical Bulletin

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The dramatic increase in the number of asthma cases over the last decades is of great concern for public health in the world.1) The CD4 ϩ T helper 2 lymphocytes (Th2 cells) are closely associated with disease severity, suggesting an integral role of Th2 cells in the pathophysiology of allergic bronchial asthma.2-5) Th2 cells secrete various cytokines, termed Th2 cytokines, which cause several key features of allergic bronchial asthma, including airway hyperresponsiveness (AHR).2-5) Increasing evidence indicates that interleukin-13 (IL-13), one of the members of Th2 cytokine family, is a crucial mediator in the development of AHR. [6][7][8] In addition, another Th2 cytokine IL-4 is also believed to play a role in asthma.9-11) Interestingly, IL-4 shares many functional properties with IL-13, presumably because they share a common receptor composed of IL4Ra chain as one of the two hetero chains. 12)Most of the activities of IL-13 and IL-4 can be ascribed to the activation of signal transducer and activator of transcription 6 (STAT6). [13][14][15] Indeed, a critical role of the STAT6 signal transduction in the development of AHR has been suggested in STAT6-deficient mice. 16,17) Similarly, a cell-penetrating dominant-negative STAT6 peptide could inhibit AHR in a mouse model of allergic bronchial asthma.18) On the other hand, recent studies also indicated an implication of the STAT family of molecules other than STAT6, such as STAT1 19) and STAT3,20) in the development of AHR. However, there is little information whether or not antigen challenge really causes the in vivo activation of these STAT molecules in bronchial smooth muscles (BSMs). In the present study, activations of these STAT molecules were examined in BSMs of a murine model of allergic asthma, which has marked BSM hyperresponsiveness. 21,22) MATERIALS AND METHODS AnimalsMale BALB/c mice were purchased from the Charles River Japan, Inc. (Kanagawa, Japan) and housed in a pathogen-free facility. All animal experiments were approved by the Animal Care Committee of the Hoshi University (Tokyo, Japan).Antigen Sensitization and Challenge Preparation of a murine model of allergic bronchial asthma was performed as described previously. [21][22][23][24][25] In brief, BALB/c mice (8 weeks of age) were actively sensitized by intraperitoneal (i.p.) injections of 8 mg ovalbumin (OA; Seikagaku Co., Tokyo, Japan) with 2 mg Imject Alum (Pierce Biotechnology, Inc., Rockfold, IL, U.S.A.) on day 0 and day 5. The sensitized mice were challenged with aerosolized OA-saline solution (5 mg/ml) for 30 min on days 12, 16 and 20. A control group of mice received the same immunization procedure except for inhaling saline aerosol instead of OA challenge. The aerosol was generated with an ultrasonic nebulizer (Nihon Kohden, Tokyo, Japan) and introduced to a Plexiglas chamber box (130ϫ200 mm, 100 mm height) in which the mice were placed. Three hours after the last OA challenge, mice were sacrificed by exsanguination from the abdominal aorta under urethane (1.6 g/kg, i.p.; Sigma-Aldric...

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“…Research of methylation or generally imprinting pattern of regulatory region of STAT6 and other genes is also very interesting due to their effect on gene expression. Furthermore, influencing gene expression represents a very exciting field for research with a promising perspective for targeted therapy, as was outlined by Darcan-Nicolaisen et al 74 in a study demonstrating inhibition of allergy inflammation and hyperreactivity by STAT6 siRNA in mice.…”

Section: Resultsmentioning

confidence: 99%

STAT6 - polymorphisms, haplotypes and epistasis in relation to atopy and asthma

Godava¹,

Vrtěl²,

Vodička³

2013

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Background. STAT6 has an important role in the IL-4 / IL-13 signalling pathway. Genome -wide association studies have shown that particular polymorphism (SNP) or haplotype variants of STAT6 as well as epigenetic gene modifications are associated with IgE level and asthma in childhood. Methods. A review of the available literature was performed to map out the function and signalling pathway of STAT6, studies of STAT6 SNPs association with susceptibility to asthma and atopy, covering the years 1997 -2012 were summarized, and the value of epigenetic and epistatic influences on STAT6 and their relevance to the development of the studied phenotype (atopy or asthma) were determined. Results. There are 2 SNPs (rs71802646 and rs320411) with clinical association and proven functional effect on STAT6 expression. The effect of STAT6 SNPs cumulates in haplotypes and more potently during interaction with SNPs in the genes from the signalling pathway (IL4, IL4Ra, and IL13). Expression of STAT6 is also influenced by DNA methylation. Atopy is traditionally believed to be maternally inherited but there is one report about paternally overtransmitted STAT6 haplotype (TCA haplotype, built from rs324011, rs3024974 and rs4559 SNPs). Conclusions. STAT6 polymorphisms and their combinations have an important influence on IgE level and development of asthma. However, the interaction between SNPs in the IL-4 / IL-13 signalling pathway is of greater impact. Hypermethylation of the STAT6 promoter is also significant in the regulation of STAT6 expression and this fact opens possibilities for targeting therapy in asthma.

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Small Interfering RNA against Transcription Factor STAT6 Inhibits Allergic Airway Inflammation and Hyperreactivity in Mice

Cited by 66 publications

References 50 publications

CD80 and CD86 knockdown in dendritic cells regulates Th1/Th2 cytokine production in asthmatic mice

CD80 and CD86 knockdown in dendritic cells regulates Th1/Th2 cytokine production in asthmatic mice

Phosphorylation of Signal Transducer and Activator of Transcription 6 (STAT6) and STAT1, but Not STAT3, Induced by Antigen Inhalation in Bronchial Smooth Muscles of Sensitized Mice

STAT6 - polymorphisms, haplotypes and epistasis in relation to atopy and asthma

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