In Vivo IL-10 Gene Delivery Suppresses Airway Eosinophilia and Hyperreactivity by Down-Regulating APC Functions and Migration without Impairing the Antigen-Specific Systemic Immune Response in a Mouse Model of Allergic Airway Inflammation

Abstract

IL-10 is an immunosuppressive cytokine. Although previous studies have reported that exogenous delivery of IL-10 reduced airway inflammation in experimental allergic airway inflammation, the mechanism of action has not been fully clarified. In this report, we elucidated a mechanism of action of IL-10 in vivo. BALB/c mice were immunized and aerosol challenged with OVA-Ag. We delivered the IL-10 gene to the mice before systemic sensitization or during aerosol Ag challenge by administering an IL-10-producing plasmid vector. Not only presensitization delivery of IL-10, as reported, but also delivery during inflammation strongly suppressed the development of airway eosinophilia and hyperreactivity. Presensitization delivery suppressed the Ag-specific Th2-type immune response in both the lung and spleen. In contrast, delivery in the effector phase suppressed the Th2 response only in the lung, whereas that in the spleen was not affected. IL-10 gene delivery did not induce the development of a regulatory phenotype of T cells or dendritic cells; rather, it suppressed the overall functions of CD11c+ APCs of the lung such as Ag-presenting capacity, cytokine production, and transportation of OVA-Ag to lymph nodes, thus attenuating Th2-mediated allergic airway inflammation. Further, IL-10 revealed a distinct immunosuppressive effect in the presence of Ag and APCs. These results suggest that suppression of APC function in the lung, the site of immune response, played a critical role in the IL-10-mediated suppression of Ag-induced airway inflammation and hyperreactivity. Therefore, if delivered selectively, IL-10 could site specifically suppress the Ag-specific immune response without affecting systemic immune responses.

Dopamine D1-Like Receptor Antagonist Attenuates Th17-Mediated Immune Response and Ovalbumin Antigen-Induced Neutrophilic Airway Inflammation

“…To generate OVA-induced eosinophilic airway inflammation, BALB/c mice were sensitized with an i.p. injection of 2 mg OVA plus 2 mg aluminum hydroxide or SA on days 220 and 29, and the mice were challenged with an aerosolized solution of 3% OVA or PBS for 10 min from day 22 to day 0 (23)(24)(25)(26). From weeks 26 to 0, some mice received SCH23390 (0.3 mg/kg) in PBS (50 ml) or PBS alone orally three times a week.…”

“…Bronchoalveolar lavage (BAL) fluid analyses were performed as previously reported (23)(24)(25)(26)(27)(28). The mice were anesthetized by i.p.…”

“…Lung CD11c + APCs were prepared using magnetic beads as previously reported (23,25,26). CD11c + cells (1.25 3 10 5 cells/well) were incubated with LPS (1 mg/ml) or LPS plus anti-CD40 Ab (5 mg/ml) for 24 h, and then cytokine concentrations in the supernatants were measured using an ELISA kit (R&D Systems).…”

High Expression of IL-22 Suppresses Antigen-Induced Immune Responses and Eosinophilic Airway Inflammation via an IL-10–Associated Mechanism

“…IL-10 is an immunosuppressive cytokine that signals through a heterodimer comprising IL-10R1 and IL-10R2 (12). We previously reported that IL-10 has a potent suppressive effect on allergic airway inflammation by downregulating APC functions and migration (13). In contrast, IL-22 transduces signals through a heterodimer comprising IL-22R1 and IL-10R2.…”

The role of dendritic cells and regulatory T cells in the regulation of allergic asthma

“…This Treg population is derived in culture and expresses the CD25 cell surface marker due to their activation in vitro in addition to producing IL-10 ( Levings et al, 2002;Martin et al, 2003;Zhang et al, 2004;Hawrylowicz, 2005;Hawrylowicz & O'Garra, 2005;MacDonald et al, 2005;Nakagome et al, 2005;Maynard et al, 2007). The in vivo generation of anergy or tolerance to antigen administration can also induce the appearance of IL-10-producing T cells (Buer et al, 1998;Burkhart et al, 1999;Sundstedt et al, 2003).…”