Ras Activation in T Cells Determines the Development of Antigen-Induced Airway Hyperresponsiveness and Eosinophilic Inflammation

Shibata, Yoshiyuki; Kamata, Tohru; Kimura, Motoko; Yamashita, Masakatsu; Wang, Chrong‐Reen; Murata, Kaoru; Miyazaki, Masaru; Taniguchi, Masaru; Watanabe, Naohiro; Nakayama, Toshinori

doi:10.4049/jimmunol.169.4.2134

Cited by 29 publications

(22 citation statements)

References 42 publications

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“…In our previous reports, we showed that Th2 cell differentiation and Th2-dependent airway inflammation are highly dependent on the TCR-mediated activation of the Ras-ERK MAPK cascade (6,48). In the present study, we detected significantly reduced activation of the Ras/MAPK cascade in aging mouse CD4 ϩ T cells (Fig.…”

Section: Discussionsupporting

confidence: 65%

“…We reported that Th2 responses are highly dependent on the extent of activation of the Ras-ERK MAPK cascade (6,48). The hyperacetylation of histones associated with the Th2 cytokine gene locus is dependent on the expression of GATA3 (43,46).…”

Section: Chromatin Remodeling Of the Th2 Cytokine Gene Locus In Cd4 ϩmentioning

confidence: 99%

“…Mice were made to inhale aerosolized OVA in saline (10 mg/ml) for 30 min. using a supersonic nebulizer (model NE-U07; Omron) on days 14 and 16 to assess eosinophilic inflammation as described previously (48).…”

Section: Sensitization and Inhalation With Ovamentioning

confidence: 99%

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Impaired GATA3-Dependent Chromatin Remodeling and Th2 Cell Differentiation Leading to Attenuated Allergic Airway Inflammation in Aging Mice

Hasegawa

Miki

Hosokawa

et al. 2006

The Journal of Immunology

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Age-related changes in lymphocytes are most prominent in the T cell compartment. There have been substantial numbers of reports on T cell function in aged mice and humans, such as on the production of Th1 and Th2 cytokines, but the results show considerable variation and contradictions. In the present study, we used 8- to 12-mo-old aging mice and a well-established in vitro Th1/Th2 cell differentiation culture system to identify molecular defects in Th1/Th2 cell differentiation that can be detected in the relatively early stages of aging. The capability to differentiate into Th2 cells is reduced in aging mouse CD4+ T cells. Decreased activation of the ERK MAPK cascade upon TCR stimulation, but normal intracellular-free calcium ion concentration mobilization and normal IL-4-induced STAT6 activation were observed in aging mouse CD4+ T cells. In addition, reduced expression of GATA3 was detected in developing Th2 cells. Chromatin remodeling of the Th2 cytokine gene locus was found to be impaired. Th2-dependent allergic airway inflammation was milder in aging mice compared with in young adult mice. These results suggest that the levels of Th2 cell differentiation and resulting Th2-dependent immune responses, including allergic airway inflammation, decline during aging through defects in the activation of the ERK MAPK cascade, expression of GATA3 protein and GATA3-dependent chromatin remodeling of the Th2 cytokine gene locus. In the present study, we provide the first evidence indicating that a chromatin-remodeling event in T cells is impaired by aging.

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Section: Discussionsupporting

confidence: 65%

Section: Chromatin Remodeling Of the Th2 Cytokine Gene Locus In Cd4 ϩmentioning

confidence: 99%

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Impaired GATA3-Dependent Chromatin Remodeling and Th2 Cell Differentiation Leading to Attenuated Allergic Airway Inflammation in Aging Mice

Hasegawa

Miki

Hosokawa

et al. 2006

The Journal of Immunology

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“…A modest (Ϸ2-fold) but reproducible increase in the number of eosinophils was detected in mice treated with OVA alone as compared with those in PBS-or LPS-treated mice. The extent of eosinophilic infiltration induced in this protocol was significantly lower than that induced by intraperitoneal immunization of OVA with alum (data not shown) (28,29). However, the numbers of total cells and eosinophils were significantly increased when wild-type ϩ͞ϩ mice were treated with both OVA and LPS.…”

mentioning

confidence: 74%

Regulation of allergic airway inflammation through Toll-like receptor 4-mediated modification of mast cell function

Nigo¹,

Yamashita²,

Hirahara³

et al. 2006

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

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136

135

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In a mouse experimental asthma model, the administration of bacterial lipopolysaccharide (LPS), particularly at low doses, enhances the levels of ovalbumin (OVA)-induced eosinophilic airway inflammation. In an effort to clarify the cellular and molecular basis for the LPS effect, we demonstrate that the OVA-induced eosinophilic inflammation in the lung is dramatically increased by the administration of LPS in wild-type mice, whereas such increase was not observed in mast-cell-deficient mice or Toll-like receptor (TLR)4-deficient mice. Adoptive transfer of bone-marrow-derived mast cells (BMMCs) from wild-type, but not from TLR4-deficient, mice restored the increased eosinophilic inflammation in mast-celldeficient mice. Wild-type BMMCs pretreated with LPS in vitro also reconstituted the eosinophilic inflammation. Moreover, in vitro analysis revealed that the treatment of BMMCs with LPS resulted in NF-B activation, sustained up-regulation of GATA1 and -2 expression, and increased the capability to produce IL-5 and -13. Dramatic increases in the expression of IL-5 and -13 and Eotaxin 2 were detected in LPS-treated BMMCs after costimulation with LPS and IgE͞Ag. Overexpression of GATA1, but not GATA2, in MC9 mast cells resulted in increased transcriptional activity of IL-4, -5, and -13. Furthermore, the levels of transcription of Th2 cytokines in BMMCs were decreased by the introduction of small interfering RNA for GATA1. Thus, mast cells appear to control allergic airway inflammation after their activation and modulation through TLR4-mediated induction of GATA1 and subsequent increase in Th2 cytokine production.cytokine ͉ GATA1 ͉ mast cell ͉ lipopolysaccharide ͉ bone-marrow-derived mast cells

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“…In this respect, MIF's ability to induce sustained ERK-1͞2 activation may be of importance (18). Activation of the ERK-1/2 mitogen-activated protein kinase (MAPK) cascade in the differentiation of T H 2 cells may be necessary for antigen-induced airway hyperreactivity and eosinophilic inflammation (38).…”

Section: Discussionmentioning

confidence: 99%

Role for macrophage migration inhibitory factor in asthma

Mizue

Ghani

Leng

et al. 2005

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

193

202

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Macrophage migration inhibitory factor (MIF) is an immunologic regulator that is expressed in inflammatory and autoimmune disorders. We investigated MIF's role in asthma using genetic approaches in a mouse model and in a cohort of asthma patients. Mice genetically deficient in MIF that were primed and aerosolchallenged with ovalbumin showed less pulmonary inflammation and lower airway hyperresponsiveness than genetically matched, wild-type controls. MIF deficiency also resulted in lower titers of specific IgE, IgG 1, and IgG2a, and decreased pulmonary, TH2 cytokine levels. IL-5 concentrations were lower and corresponded to decreased eosinophil numbers in bronchoalveolar lavage fluid. T cell studies also showed a lower level of antigen-specific responses in MIF-KO versus wild-type mice. In an analysis of 151 white patients with mild, moderate, or severe asthma (Global Initiative for Asthma criteria), a significant association was found between mild asthma and the low-expression, 5-CATT MIF allele. Pharmacologic inhibition of MIF may be beneficial and could be guided by the MIF genotype of affected individuals.cytokine ͉ genetic polymorphism ͉ innate immunity

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Ras Activation in T Cells Determines the Development of Antigen-Induced Airway Hyperresponsiveness and Eosinophilic Inflammation

Cited by 29 publications

References 42 publications

Impaired GATA3-Dependent Chromatin Remodeling and Th2 Cell Differentiation Leading to Attenuated Allergic Airway Inflammation in Aging Mice

Impaired GATA3-Dependent Chromatin Remodeling and Th2 Cell Differentiation Leading to Attenuated Allergic Airway Inflammation in Aging Mice

Regulation of allergic airway inflammation through Toll-like receptor 4-mediated modification of mast cell function

Role for macrophage migration inhibitory factor in asthma

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