IL-12 overexpression in mice as a model for Sjogren lung disease

IL-12 overexpression in mice as a model for Sjogren lung disease. Am J Physiol Lung Cell Mol Physiol 291: L837-L846, 2006. First published June 2, 2006; doi: 10.1152/ajplung. 00134.2006.-Interleukin-12 (IL-12), a Th1 proinflammatory cytokine, is reported to be increased in Sjogren syndrome. To evaluate the effects of local Th1/Th2 deregulation, we generated a transgenic mouse model that overexpresses IL-12 in the lungs. IL-12 transgenic mice developed bronchial and alveolar abnormalities strikingly similar to those found in the lungs of Sjogren patients. Pathologically, lung abnormalities began at similar to 4 mo of age and were characterized by lymphocytic infiltrates around the bronchi, intraluminal periodic acid Schiff-positive debris, increased cell proliferation in the alveolar region, and increased interstitial and alveolar macrophages. Functionally, these abnormalities translated into decreased mucociliary clearance (P < 0.05 vs. wild-type littermates) and increased oxidative stress (P < 0.01). The pathological and functional abnormalities were accompanied by significant changes in lung natural killer (NK) cells. The number of NK cells was fourfold higher in IL-12 transgenic than wild-type lungs (20% of all lymphoid cells vs. 5%) during the first month of life. NK cells then decreased within a narrow window of time (from 30 to 50 days of age), reaching a nadir of similar to 2% on day 50, and remained at these low levels thereafter. This new mouse model highlights the role of IL-12 in the initiation of Sjogren syndrome.