T helper 1 cells stimulated with ovalbumin and IL-18 induce airway hyperresponsiveness and lung fibrosis by IFN- and IL-13 production

Department of Immunology and Medical Zoology, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 10/2007; 104(37):14765-70. DOI: 10.1073/pnas.0706378104
Source: PubMed


We previously reported that ovalbumin (OVA) and IL-18 nasally administered act on memory type T helper (Th)1 cells to induce airway hyperresponsiveness (AHR) and inflammation, which is characterized by peribronchial infiltration with neutrophils and eosinophils. Here, we report this administration also induces lung fibrosis in an IL-13-dependent manner. Th1 cells secrete several cytokines, including IFN-gamma and bronchogenic cytokine IL-13, when stimulated with antigen (Ag) and IL-18. However, IL-13 blockade failed to attenuate AHR, although this treatment inhibited eosinophilic infiltration. To understand the mechanism by which Th1 cells induce AHR after Ag plus IL-18 challenge, we established "passive" and "active" Th1 mice by transferring OVA-specific Th1 cells into naïve BALB/c mice or by immunizing naïve BALB/c mice with OVA/complete Freund's adjuvant, respectively. Administration of Ag and IL-18 induced both types of Th1 mice to develop AHR, airway inflammation, and lung fibrosis. Furthermore, this treatment induced deposition of periostin, a novel component of lung fibrosis. Neutralization of IL-13 or IFN-gamma during Ag plus IL-18 challenges inhibited the combination of eosinophilic infiltration, lung fibrosis, and periostin deposition or the combination of neutrophilic infiltration and AHR, respectively. We also found that coadministration of OVA and LPS into Th1 mice induced AHR and airway inflammation via endogenous IL-18. Thus, IL-18 becomes a key target molecule for the development of a therapeutic regimen for the treatment of Th1-cell-induced bronchial asthma.

Download full-text


Available from: Toshio Tanaka
  • Source
    • "CBRM1/5 α M I domain High-activity Oxvig et al. (1999), Byron et al. (2009) EGF, epidermal growth factor; PSI, plexin-semaphorin-integrin. type 2 (Th2) cytokines in bronchial epithelial cells and lung fibroblasts and is deposited in patients with asthma and atopic dermatitis, as well as in animal models of asthma and allergic skin inflammation (Yuyama et al., 2002; Takayama et al., 2006; Hayashi et al., 2007; Woodruff et al., 2007; Masuoka et al., 2012). Mice lacking periostin respond to lung antigen challenge with significantly decreased number of eosinophils in the lung and have reduced allergic skin inflammation (Blanchard et al., 2008; Bentley et al., 2012; Masuoka et al., 2012), thus implicating periostin as a ligand in eosinophil recruitment and retention in allergy and asthma. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Eosinophil arrest and recruitment to the airway in asthma are mediated, at least in part, by integrins. Eosinophils express α4β1, α6β1, αLβ2, αMβ2, αXβ2, αDβ2, and α4β7 integrins, which interact with counter-receptors on other cells or ligands in the extracellular matrix. Whether a given integrin-ligand pair mediates cell adhesion and migration depends on the activation state of the integrin. Integrins exist in an inactive bent, an intermediate-activity extended closed, and a high-activity extended open conformation. Integrin activation states can be monitored by conformation-specific monoclonal antibodies (mAbs). Studies in mice indicate that both β1 and β2 integrins mediate eosinophil recruitment to the lung. In vitro studies indicate that α4β1 and αMβ2 are the principal integrins mediating eosinophil adhesion, including to vascular cell adhesion molecule-1 and the novel αMβ2 ligand periostin. In vivo, blood eosinophils have intermediate-activity β1 integrins, as judged by mAb N29, apparently resulting from eosinophil binding of P-selectin on the surface of activated platelets, and have a proportion of their β2 integrins in the intermediate conformation, as judged by mAb KIM-127, apparently due to exposure to low concentrations of interleukin-5 (IL-5). Airway eosinophils recovered by bronchoalveolar lavage (BAL) after segmental antigen challenge have high-activity β1 integrins and high-activity αMβ2 that does not require IL-5. Here we review information on how the activation states of eosinophil β1 and β2 integrins correlate with measurements of eosinophil recruitment and pulmonary function in asthma. Blood eosinophil N29 reactivity is associated with decreased lung function under various circumstances in non-severe asthma and KIM-127 with BAL eosinophil numbers, indicating that intermediate-activity α4β1 and αMβ2 of blood eosinophils are important for eosinophil arrest and consequently for recruitment and aspects of asthma.
    Full-text · Article · Apr 2013 · Frontiers in Pharmacology
  • Source
    • "Elevated serum IFNγ correlates with the severity of airway inflammation in atopic asthma, and this cytokine has been linked to mechanisms that induce airway hyperreactivity [43, 44]. In agreement with the findings in human asthma, it was shown that both IFNγ and LPS contribute to airway inflammation and airway hyperreactivity in a mouse model of asthma [45, 46]. TNFα is implicated in many aspects of asthma pathology, including development of airway hyperreactivity and attraction of eosinophils and neutrophils [47, 48]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Macrophages are among the most abundant cells in the respiratory tract, and they can have strikingly different phenotypes within this environment. Our knowledge of the different phenotypes and their functions in the lung is sketchy at best, but they appear to be linked to the protection of gas exchange against microbial threats and excessive tissue responses. Phenotypical changes of macrophages within the lung are found in many respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis. This paper will give an overview of what macrophage phenotypes have been described, what their known functions are, what is known about their presence in the different obstructive and restrictive respiratory diseases (asthma, COPD, pulmonary fibrosis), and how they are thought to contribute to the etiology and resolution of these diseases.
    Full-text · Article · Feb 2013 · Mediators of Inflammation
  • Source
    • "A recent study indicated that IFN-γ plays a key role in the progression of tissues fibrosis and remodeling [45]. The neutralization of IFN-γ during antigen challenge with antigen plus IL-18 inhibited both lung fibrosis and periostin deposition and both neutrophilic infiltration and airway hyperresponsiveness, respectively [46]. Shi L et al. focused on the effects of the local blockade of the TSLP receptor on acute OVA-induced airway inflammation [22], whereas our research aimed to examine the role of TSLP in HDM-induced airway remodeling, which is characterized by subepithelial fibrosis and peribronchial collagen deposition, ultimately resulting in the upregulation of IFN-γ expression in the lung. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic allergic asthma is characterized by Th2-typed inflammation, and contributes to airway remodeling and the deterioration of lung function. However, the initiating factor that links airway inflammation to remodeling is unknown. Thymic stromal lymphopoietin (TSLP), an epithelium-derived cytokine, can strongly activate lung dendritic cells (DCs) through the TSLP-TSLPR and OX40L-OX40 signaling pathways to promote Th2 differentiation. To determine whether TSLP is the underlying trigger of airway remodeling in chronic allergen-induced asthma, we induced allergic airway inflammation in mice by intranasal administration of house dust mite (HDM) extracts for up to 5 consecutive weeks. We showed that repeated respiratory exposure to HDM caused significant airway eosinophilic inflammation, peribronchial collagen deposition, goblet cell hyperplasia, and airway hyperreactivity (AHR) to methacholine. These effects were accompanied with a salient Th2 response that was characterized by the upregulation of Th2-typed cytokines, such as IL-4 and IL-13, as well as the transcription factor GATA-3. Moreover, the levels of TSLP and transforming growth factor beta 1 (TGF-β1) were also increased in the airway. We further demonstrated, using the chronic HDM-induced asthma model, that the inhibition of Th2 responses via neutralization of TSLP with an anti-TSLP mAb reversed airway inflammation, prevented structural alterations, and decreased AHR to methacholine and TGF-β1 level. These results suggest that TSLP plays a pivotal role in the initiation and persistence of airway inflammation and remodeling in the context of chronic allergic asthma.
    Preview · Article · Jan 2013 · PLoS ONE
Show more