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J. Biol. Chem., Vol. 277, Issue 38, 35466-35474, September 20, 2002
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From the 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-4R The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AF218819.
Transgenic Overexpression of Interleukin (IL)-10 in
the Lung Causes Mucus Metaplasia, Tissue Inflammation, and Airway
Remodeling via IL-13-dependent and -independent
Pathways*
,,
,,, and§§
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 Division of Infectious
Diseases, Vanderbilt University School of Medicine,
Nashville, Tennessee 37232-2582
, 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-4R/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.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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