Transgenic Overexpression of Interleukin (IL)-10 in the Lung Causes Mucus Metaplasia, Tissue Inflammation, and Airway Remodeling via IL-13-dependent and -independent Pathways

doi:10.1074/jbc.M206395200

Transgenic Overexpression of Interleukin (IL)-10 in the Lung Causes Mucus Metaplasia, Tissue Inflammation, and Airway Remodeling via IL-13-dependent and -independent Pathways*

From the ^‡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

Abstract

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-4Rα, 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-4Rα/STAT-6 activation pathway.

Footnotes

↵* 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 GenBank™/EBI Data Bank with accession number(s) .
↵§§ 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.
Published, JBC Papers in Press, July 9, 2002, DOI 10.1074/jbc.M206395200
↵2 C. G. Lee and J. A. Elias, unpublished observation.
Abbreviations:

IL

interleukin

STAT

signal transducers and activators of transcription

RSV

respiratory syncytial virus

IL-4R

interleukin-4 receptor

IL-13R

interleukin-13 receptor

VV

vaccinia virus

RPA

ribonuclease protection assay

IFN

interferon

BAL

bronchoalveolar lavage

TGF

transforming growth factor

ELISA

enzyme-linked immunosorbent assay

TNF

tumor necrosis factor

LPS

lipopolysaccharide

HMI

histologic mucus index

TTBS

Tris-buffered saline with Tween 20

PAS

periodic acid-Schiff with diastase

WT

wild-type

rtTA

reverse tetracycline transactivator

hGH

human growth hormone

PBS

phosphate-buffered saline

RT

reverse transcription

FITC

fluorescein isothiocyanate

PE

phycoerythrin
- Received June 27, 2002.
The American Society for Biochemistry and Molecular Biology, Inc.