Hidefumi Wakashin

IL-23 and Th17 Cells Enhance Th2-Cell–mediated Eosinophilic Airway Inflammation in Mice

RATIONALE The IL-23-IL-17A-producing CD4(+) T-cell (Th17 cell) axis plays an important role in the development of chronic inflammatory diseases, including autoimmune diseases. However, the role of the IL-23-Th17 cell axis in the regulation of allergic airway inflammation is still largely unknown. OBJECTIVES To determine the role of IL-23 and Th17 cells in allergic airway inflammation. METHODS We examined the effect of anti-IL-23 antibody on antigen-induced airway inflammation. We also investigated the effect of enforced expression of IL-23 on allergic airway inflammation by generating lung-specific IL-23 transgenic mice. Moreover, we examined the effect of adoptive transfer of antigen-specific Th17 cells on allergic airway inflammation. MEASUREMENTS AND MAIN RESULTS IL-23 mRNA was expressed in the lung of sensitized mice upon antigen inhalation, and the neutralization of IL-23 decreased antigen-induced eosinophil recruitment and Th2 cytokine production in the airways. The enforced expression of IL-23 in the airways significantly enhanced antigen-induced eosinophil and neutrophil recruitment into the airways; Th2 cytokine, IL-17A, and tumor necrosis factor (TNF)-alpha production in the airways; goblet cell hyperplasia; and airway hyperresponsiveness. Moreover, IL-23-mediated enhancement of antigen-induced Th2 cytokine production and eosinophil recruitment in the airways was still observed in the mice lacking IL-17A. Furthermore, although adoptive transfer of antigen-specific Th17 cells alone induced neutrophil but not eosinophil recruitment into the airways upon antigen inhalation, cotransfer of Th17 cells with Th2 cells significantly enhanced antigen-induced Th2-cell-mediated eosinophil recruitment into the airways and airway hyperresponsiveness. CONCLUSIONS IL-23 and Th17 cells not only induce Th17-cell-mediated neutrophilic airway inflammation but also up-regulate Th2-cell-mediated eosinophilic airway inflammation.

IL-22 attenuates IL-25 production by lung epithelial cells and inhibits antigen-induced eosinophilic airway inflammation.

BACKGROUND IL-22 functions as both a proinflammatory cytokine and an anti-inflammatory cytokine in various inflammations, depending on the cellular and cytokine milieu. However, the roles of IL-22 in the regulation of allergic airway inflammation are still largely unknown. OBJECTIVE We sought to determine whether IL-22 is involved in the regulation of allergic airway inflammation. METHODS We examined IL-22 production and its cellular source at the site of antigen-induced airway inflammation in mice. We also examined the effect of IL-22 neutralization, as well as IL-22 administration, on antigen-induced airway inflammation. We finally examined the effect of IL-22 on IL-25 production from a lung epithelial cell line (MLE-15 cells). RESULTS Antigen inhalation induced IL-22 production in the airways of sensitized mice. CD4(+) T cells, but not other lymphocytes or innate cells, infiltrating in the airways produced IL-22, and one third of IL-22-producing CD4(+) T cells also produced IL-17A. The neutralization of IL-22 by anti-IL-22 antibody enhanced antigen-induced IL-13 production, eosinophil recruitment, and goblet cell hyperplasia in the airways. On the other hand, intranasal administration of recombinant IL-22 attenuated antigen-induced eosinophil recruitment into the airways. Moreover, anti-IL-22 antibody enhanced antigen-induced IL-25 production in the airways, and anti-IL-25 antibody reversed the enhancing effect of anti-IL-22 antibody on antigen-induced eosinophil recruitment into the airways. Finally, IL-22 inhibited IL-13-mediated enhancement of IL-25 expression in IL-1β- or LPS-stimulated MLE-15 cells. CONCLUSION IL-22 attenuates antigen-induced airway inflammation, possibly by inhibiting IL-25 production by lung epithelial cells.

Role of IL-23-Th17 Cell Axis in Allergic Airway Inflammation

Asthma is characterized by chronic airway inflammation with intense eosinophil and lymphocyte infiltration, mucus hyperproduction, and airway hyperresponsiveness to a variety of stimuli. It is now generally accepted that antigen-specific Th2 cells and their cytokines orchestrate these pathognomonic features of asthma. On the other hand, Th17 cells and IL-23, a cytokine that preferentially expands Th17 cells, play a significant role in the development of chronic inflammatory diseases, including autoimmune diseases. Recently, we have shown that IL-23 and Th17 cells enhance not only neutrophilic airway inflammation but also Th2 cell-mediated eosinophilic airway inflammation in a murine asthma model. In this review, we will discuss the roles of IL-23 and Th17 cells in airway inflammation in asthma.

STAT4 Is Required for IFN-β-Induced MCP-1 mRNA Expression in Murine Mast Cells

Background: Mast cells are immunocompetent cells that are found in almost all tissues and function as sentinels of immune responses. Recently, it has been shown that mast cells play significant roles in innate immune responses. However, it is still largely unknown whether signal transducers and activators of transcription 4 (STAT4), one of the STAT proteins under type I IFN signaling, is involved in type I IFN-mediated gene expression in mast cells. Methods: We investigated the role of STAT4 in IFN-β-induced gene expression in mast cells by using STAT4-deficient (STAT4–/–) bone marrow-derived mast cells (BMMCs). Results: STAT4 was expressed in BMMCs and activated in response to IFN-β but not to IL-12 or IL-23. The development of BMMCs as well as IgE-induced degranulation of BMMCs was normal in STAT4–/– mice. On the other hand, while IFN-β-induced mRNA expression of interferon-induced protein with tetratricopeptide repeats 1 (IFIT-1), protein kinase interferon-inducible double stranded RNA dependent (PKR), and myxovirus resistance 1 (Mx1) was similar between STAT4–/– BMMCs and wild-type (WT) BMMCs, IFN-β-induced MCP-1 mRNA expression was severely diminished in STAT4–/– BMMCs as compared with WT BMMCs. Conclusions: STAT4 plays an essential role in IFN-β-induced MCP-1 mRNA expression in mast cells.

GS143, an IκB ubiquitination inhibitor, inhibits allergic airway inflammation in mice ☆

Asthma is characterized by airway inflammation with intense eosinophil infiltration and mucus hyper-production, in which antigen-specific Th2 cells play critical roles. Nuclear factor-kappaB (NF-kappaB) pathway has been demonstrated to be essential for the production of Th2 cytokines and chemokines in the airways in murine asthma models. In the present study, we examined the effect of GS143, a novel small-molecule inhibitor of IkappaB ubiquitination, on antigen-induced airway inflammation and Th2 cytokine production in mice. Intranasal administration of GS143 prior to antigen challenge suppressed antigen-induced NF-kappaB activation in the lung of sensitized mice. Intranasal administration of GS143 also inhibited antigen-induced eosinophil and lymphocyte recruitment into the airways as well as the expression of Th2 cytokines and eotaxin in the airways. Moreover, GS143 inhibited antigen-induced differentiation of Th2 cells but not of Th1 cells in vitro. Taken together, these results suggest that IkappaB ubiquitination inhibitor may have therapeutic potential against asthma.