IL-33 precursor drives inflammation without engaging T1/ST2 or Th2
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1
University of Maryland School of Medicine, United States
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2
Baltimore VA Medical Center, United States
Interstitial lung disease, a combination of chronic pulmonary inflammation and excessive scarring, is debilitating and deadly, particularly in patients with systemic sclerosis (SSc) or idiopathic pulmonary fibrosis (IPF). Immunohistochemical analyses of lung sections from five patients with SSc and nine patients with IPF revealed a marked increase in the numbers of IL-33-expressing cells compared with four healthy controls. Much of the elevated IL-33 was intracellular, and there were minimal signs of Th2 activation, suggesting that precursor IL-33 (PRIL33), rather than mature IL-33 cytokine (MIL33), was increased. Western blot assays of lung tissue homogenates confirmed minimal maturation of PRIL33 into MIL33. Analysis of the subcellular distribution of overexpressed IL-33 forms in normal primary fibroblast cell cultures revealed that PRIL33 is localized almost exclusively (>95%) in the cell nucleus and is not secreted from the cells, whereas MIL33 is predominantly cytoplasmic and secreted. Recombinant adenoviral gene delivery of PRIL33 and MIL33 to mouse lungs resulted in strikingly different phenotypes: PRIL33 induced pulmonary lymphocytosis and neutrophilia, whereas MIL33 induced eosinophilia, goblet cell hyperplasia, and increases in IL-4, IL-5, IL-13, and IL-17. Germline deficiency of the MIL33 receptor T1/ST2 abrogated the effects of MIL33 gene delivery but not the effects of PRIL33 delivery. Gene delivery of MIL33 in cell culture and in vivo caused elevation of the expression of CCL2, IL-6, MMP3, MMP10, MMP13, and HSP70 mRNAs and proteins, which are all known to contribute to inflammation and scarring. Thus, the IL-33 precursor can drive inflammation by remaining intranuclear and regulating gene expression.
Keywords:
interleukin-33,
Inflammation,
Fibrosis,
Lung,
Scleroderma, Systemic,
Idiopathic Pulmonary Fibrosis
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Immune-mediated disease pathogenesis
Citation:
Luzina
IG,
Lockatell
V,
Todd
NW and
Atamas
SP
(2013). IL-33 precursor drives inflammation without engaging T1/ST2 or Th2.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.00860
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Received:
18 Jun 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Dr. Sergei P Atamas, University of Maryland School of Medicine, Baltimore, Maryland, United States, satamas@som.umaryland.edu