Transgenic overexpression of interleukin (IL)-10 in the lung causes mucus metaplasia, tissue inflammation, and airway remodeling via IL-13-dependent and -independent pathways.
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(alpha), 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(alpha)/STAT-6 activation pathway.
Lee
Chun Geun
CG
Section of Pulmonary and Critical Care Medicine, Department. of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8057, USA.
Homer
Robert J
RJ
Cohn
Lauren
L
Link
Holger
H
Jung
Sungsoo
S
Craft
Joseph E
JE
Graham
Barney S
BS
Johnson
Teresa R
TR
Elias
Jack A
JA
D000818:Animals; D001483:Base Sequence; D018118:Chloride Channels / Q000235:genetics; D003001:Cloning, Molecular; D017931:DNA Primers; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D017403:In Situ Hybridization; D007249:Inflammation / Q000235:genetics*; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism*; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009088:Mucoproteins / Q000235:genetics; D009092:Mucous Membrane / Q000473:pathology; D010641:Phenotype; D016133:Polymerase Chain Reaction; D019948:Receptors, Interleukin-4 / Q000502:physiology; D050800:STAT6 Transcription Factor; D015534:Trans-Activators / Q000502:physiology
D018118:Chloride Channels; C116464:Clca3a1 protein, mouse; D017931:DNA Primers; D018793:Interleukin-13; D009088:Mucoproteins; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D016753:Interleukin-10