IL-12 overexpression in mice as a model for Sjögren lung disease.
Interleukin-12 (IL-12), a Th1 proinflammatory cytokine, is reported to be increased in Sjögren 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 Sjögren patients. Pathologically, lung abnormalities began at approximately 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 approximately 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 Sjögren syndrome.
McGrath-Morrow
Sharon
S
Department of Pediatrics, The Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Laube
Beth
B
Tzou
Shey-Cherng
SC
Cho
Cecilia
C
Cleary
Jeffrey
J
Kimura
Hiroaki
H
Rose
Noel R
NR
Caturegli
Patrizio
P
D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000473:pathology; D007765:Lacrimal Apparatus / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008171:Lung Diseases / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D008214:Lymphocytes / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009079:Mucociliary Clearance; D018384:Oxidative Stress; D010503:Periodic Acid-Schiff Reaction; D012469:Salivary Glands / Q000473:pathology; D015398:Signal Transduction; D012859:Sjogren's Syndrome / Q000150:complications*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D016212:Transforming Growth Factor beta; D018664:Interleukin-12