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Originally published In Press as doi:10.1074/jbc.M206395200 on July 9, 2002

J. Biol. Chem., Vol. 277, Issue 38, 35466-35474, September 20, 2002
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Transgenic Overexpression of Interleukin (IL)-10 in the Lung Causes Mucus Metaplasia, Tissue Inflammation, and Airway Remodeling via IL-13-dependent and -independent Pathways*

Chun Geun LeeDagger , Robert J. Homer§, Lauren CohnDagger , Holger Link, Sungsoo Jung||, Joseph E. Craft**, Barney S. GrahamDagger Dagger , Teresa R. JohnsonDagger Dagger , and Jack A. EliasDagger §§

From the Dagger  Section of Pulmonary and Critical Care Medicine, Department. of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8057, the § Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520 and the Pathology and Laboratory Medicine Service, Veterans Administration Connecticut Health Care System, West Haven, Connecticut 06516, the  Section of Respiratory Medicine, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06520-8057, the || Division of Rheumatology, Hanyang University Medical College and Hospital for Rheumatic Disease, 17 Hangdang-dong, Sungdong-gu, Seoul 133-792, South Korea, the ** Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-08057, and the Dagger Dagger  Division of Infectious Diseases, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2582

To address the complex chronic effector properties of interleukin (IL)-10, we generated transgenic mice in which IL-10 was overexpressed in the lung. In these mice, IL-10 inhibited endotoxin-induced tumor necrosis factor production and neutrophil accumulation. IL-10 also caused mucus metaplasia, B and T cell-rich inflammation, and subepithelial fibrosis and augmented the levels of mRNA encoding Gob-5, mucins, and IL-13. In mice bred to have null mutations of IL-13, IL-4Ralpha , or STAT-6, transgenic IL-10 did not induce mucus metaplasia but did induce inflammation and fibrosis. IL-10 was also a critical mucin regulator of virus-induced mucus metaplasia. Thus, IL-10, although inhibiting lipopolysaccharide-induced inflammation, also causes mucus metaplasia, tissue inflammation, and airway fibrosis. These responses are mediated by multiple mechanisms with mucus metaplasia being dependent on and the inflammation and fibrosis being independent of an IL-13/IL-4Ralpha /STAT-6 activation pathway.

* This work was supported by National Institutes of Health Grants HL-56389, HL-61904, HL-64242 (to J. A. E.), and HL-6404 (to L. C.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AF218819.

§§ To whom correspondence should be addressed: Dept. of Internal Medicine, Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, 333 Cedar St., 105 LCI, P. O. Box 208057, New Haven, CT 06520-8057. Tel.: 203-785-4163; Fax: 203-785-3826; E-mail: jack.elias@yale.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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