Interleukin 12 inhibits antigen-induced airway hyperresponsiveness, inflammation, and Th2 cytokine expression in mice.

Abstract

SummaryAllergic asthma is characterized by airway hyperresponsiveness and pulmonary eosinophilia, and may be mediated by T helper (Th) lymphocytes expressing a Th2 cytokine pattern. Interleukin (IL) 12 suppresses the expression of Th2 cytokines and their associated responses, including eosinophilia, serum immunoglobulin E, and mucosal mastocytosis. We have previously shown in a routine model that antigen-induced increases in airway hyperresponsiveness and pulmonary eosinophilia are CD4 + T cell dependent. We used this model to determine the ability of IL-12 to prevent antigen-induced increases in airway hyperresponsiveness, bronchoalveolar lavage (BAL) eosinophils, and lung Th2 cytokine expression. Sensitized A/J mice developed airway hyperresponsiveness and increased numbers of BAL eosinophils and other inflammatory cells after single or repeated intratracheal challenges with sheep red blood cell antigen. Pulmonary mKNA and protein levels of the Th2 cytokines IL-4 and IL-5 were increased after antigen challenge. Administration oflL-12 (1 p,g/d • 5 d) at the time of a single antigen challenge abolished the airway hyperresponsiveness and pulmonary eosinophilia and promoted an increase in interferon (IFN) ~ and decreases in IL-4 and IL-5 expression. The effects of IL-12 were partially dependent on IFN-3~, because concurrent treatment with IL-12 and anti-IFN-~/monoclonal antibody partially reversed the inhibition of airway hyperresponsiveness and eosinophilia by IL-12. Treatment of mice with IL-12 at the time of a second antigen challenge also prevented airway hyperresponsiveness and significantly reduced numbers of BAL inflammatory cells, reflecting the ability of IL-12 to inhibit responses associated with ongoing antigen-induced pulmonary inflammation. These data show that antigen-induced airway hyperresponsiveness and inflammation can be blocked by IL-12, which suppresses Th2 cytokine expression. Local administration of IL-12 may provide a novel immunotherapy for the treatment of pulmonary allergic disorders such as atopic asthma.

Exacerbated Th2‐mediated airway inflammation and hyperresponsiveness in autoimmune diabetes‐prone NOD mice: a critical role for CD1d‐dependent NKT cells

“…Several reports point to a role of IFN-+ -secreting Th1 cells in the modulation of Th2-mediated allergic inflammatory responses [18,31,32]. Since IFN-+ was not detected in lungs and BALF of either strain, it cannot account for the differences observed.…”

Targeting ST2L Potentiates CpG-Mediated Therapeutic Effects in a Chronic Fungal Asthma Model

“…The blockade of ST2L significantly enhanced the generation of IL-12p70 by CpG-activated DCs, thereby enhancing levels of a cytokine known to potently inhibit allergic asthma in mice. 43 Thus, ST2L activation contributes to experimental allergic asthma via two distinct mechanisms: the promotion of Th2-type responses and the negative regulation of TLR9 signaling.…”

“…allergic asthma, 43 including attenuation of asthmatic responses driven by both fungus 37 and fungal proteases. 54 The role of MIG/CXCL9 in asthma is less clear, but this CXC chemokine is strongly induced by IL-12.…”

A single administration of interleukin-4 antagonistic mutant DNA inhibits allergic airway inflammation in a mouse model of asthma

“…Administration of the Th1-associated cytokines IL-12 and interferon-g (IFN-g) has been shown to inhibit allergic inflammation in asthma. [16][17][18] Inhibition of the action of IL-4 for treatment of allergic inflammation in a mouse model has been achieved in another trial on inhibition of Th2-type responses. In studies using a neutralizing antibody (Ab) to IL-4 during sensitization or mice deficient in IL-4, the development of airway eosinophilia, AHR and the increase in serum IgE seen following sensitization were reduced or abolished.…”