Interleukin 12 p40 production by barrier epithelial cells during airway inflammation

Human airway epithelial cells appear specially programmed for expression of immune response genes implicated in immunity and inflammation. To better d etermine how this epithelial system operates in vivo, we analyzed its behav ior in mouse models that allow for in vitro versus in vivo comparison and g enetic modification. Initial comparisons indicated that tumor necrosis fact or alpha induction of epithelial intercellular adhesion molecule 1 required sequential induction of interleukin (IL)-12 (p70) and interferon gamma, an d unexpectedly localized IL-12 production to airway epithelial cells. Epith elial IL-12 was also inducible during paramyxoviral bronchitis, but in this case, initial IL-12 p70 expression was followed by 75-fold greater express ion of IL-12 p40 (as monomer and homodimer). Induction of IL-12 p40 was eve n further increased in IL-12 p35-deficient mice, and in this case. was asso ciated with increased mortality and epithelial macrophage accumulation. The results placed epithelial cell overgeneration of IL-12 p40 as a key interm ediate for virus-inducible inflammation and a candidate for epithelial immu ne response genes that are abnormally programmed in inflammatory disease. T his Possibility was further supported when we observed IL-12 p40 overexpres sion selectively in airway epithelial cells in subjects with asthma and con comitant increases in airway levels of IL-12 p40 (as homodimer) and airway macrophages. Taken together, these results suggest a novel role for epithel ial-derived IL-12 p40 in modifying the level of airway inflammation during mucosal defense and disease.