Prevention of IL-1 signaling attenuates airway hyperresponsiveness and inflammation in a murine model of toluene diisocyanate-induced asthma

Background: IL-1 is a pleotropic cytokine that has been shown to play a prominent role in asthma induced by large molecular-weight proteins. Increased IL-1 inummostaining in the submucosa of patients with toluene diisocyanate (TDI)-induced asthma has also been observed, suggesting that this cytokine might also be important in asthma associated with low-molecular-weight chemicals. Objective: We sought to determine the role of IL-1 signaling in airway reactivity and inflammation by using a marine model of TDI-induced asthma. Methods: C57BL/6 mice were exposed to TDI by means of vapor inhalation (20 ppb; 4 hours per day, 5 days per week, for 6 weeks) and then challenged 2 weeks later by inhalation with 20 ppb TDI vapor for 1 hour. Results: Sensitized-challenged mice showed increased airway hyperresponsiveness (AHR), increased levels of TDI-specific IgG(1) antibodies, airway epithelial thickening, inflammation consisting of infiltrating lymphocytes and eosinophils, and increased mRNA expression of IL-4, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 in the lung. Prevention of IL-1 signaling through deletion of the IL-1 receptor type I or administration of neutralizing antibodies to both IL-1P and IL-1 alpha abrogated the development of TDI-induced asthma. A partial reduction in AHR and TDI-specific IgG(1) levels was observed in mice administered anti-IL-1p, whereas anti-IL-1 alpha had no effect on either parameter. Antibodies to IL-1 beta or IL-1 alpha alone blocked airway inflammation and the expression of IL-4 and adhesion molecules in the lung. Conclusions: These results suggest that IL-1 signaling is critical for AHR and airway inflammation, with wIL-1 beta and IL-1 alpha having unique and overlapping roles in TDI-induced occupational asthma.