IL-12 alleviates allergic lung inflammation in the absence of T-bet regulation

Allergic asthma has long been characterized by pulmonary eosinophilia and AHR mediated by Th2 cells. The Th1/Th2 paradigm has been the basis for many therapeutic approaches in regulating asthmatic responses and numerous studies have compellingly demonstrated that Th1 cells can inhibit the development of Th2-mediated airway inflammation. However, therapeutic strategies based on the Th1/Th2 model have thus far led to disappointing outcomes in asthmatic patients, and recent studies demonstrate that less than 50% of asthmatics suffer from eosinophilic airway inflammation. These results suggest that there is an incomplete understanding of the mechanisms mediating the asthmatic response.Th17 cells producing IL-17 have been implicated in a number of inflammatory diseases, including autoimmune and allergic inflammation. Here, the role of Th17 cells in the development of allergic asthma was investigated. Of particular interest are recent studies demonstrating that T-bet, a T-box transcription factor crucial for Th1 cell differentiation and IFN-gamma production, is significantly decreased in the airways of asthmatic patients and that polymorphisms of this gene in humans are correlated with airway inflammation and AHR. In this study, it is hypothesized that in the absence of T-bet, the Th cell response which leads to pulmonary inflammation and AHR following allergen challenge, is predominantly Th1 7-mediated.Furthermore, IL-12, a Th1-inducing cytokine, was used to target Th17 cell-mediated lung inflammation in our T-bet deficient OVA asthma model. In this study, it was hypothesized that IL-12 would have an IFN-gamma-independent effect on alleviating allergic lung inflammation. The results demonstrate that there was little to no IFN-gamma expression following IL-12 treatment during the OVA-challenge phase in the absence of T-bet however, antigen-induced airway inflammation as well as AHR was almost completely abrogated. Surprisingly, this suppression was found to be IL-10-dependent. These results suggest that in a Th17 cell-mediated model, IL-12 has a strong immunosuppressive, IFN-gamma-independent effect and represent a novel mechanistic advance in which IL-12 inhibits pro-inflammatory Th17 cytokine production through induction of IL-10.