Immunoregulatory effects of regulated, lung-targeted expression of IL-10 in vivo

Donn Spight, Bin Zhao, Michael Haas, Susan Wert, Alvin Denenberg, Thomas P. Shanley

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Regulation of pulmonary inflammation involves an intricate balance of both pro- and anti-inflammatory mediators. Acute lung injury can result from direct pulmonary insults that activate alveolar macrophages to respond with increased cytokine expression. Such cytokine gene expression is mediated in part via NF-κB. IL-10 has been previously identified as an important endogenous anti-inflammatory cytokine in vivo on the basis of inhibiting NF-κB activation; however, the mechanism of this inhibition remains incompletely defined. We hypothesized that IL-10 regulated NF-κB activation in vivo via IκK inhibition. A bitransgenic mouse that allowed for externally regulated, lung-specific human IL-10 overexpression was generated. In the bitransgenic mice, introduction of doxycycline induced lung-specific, human IL-10 overexpression. Acute induction of IL-10 resulted in significant decreases in bronchoalveolar lavage fluid neutrophils (48%, P = 0.03) and TNF (62%, P < 0.01) following intratracheal LPS compared with bitransgenic negative mice. In vitro kinase assays showed this decrease to correlate to diminished lung IκK activity. Furthermore, we also examined the effect of chronic IL-10 overexpression in these transgenic mice. Results show that IL-10 overexpression in lungs of mature mice increased the number of intrapulmonary cells the phenotype of which was skewed toward increased B220+/CD45+ B cells and CD4+ T cells and was associated with increased CC chemokine expression. Thus regulated, lung-specific IL-10 overexpression may have a variety of complex immunologic effects depending on the timing and duration of expression.

Original languageEnglish (US)
Pages (from-to)L251-L265
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume288
Issue number2 32-2
DOIs
StatePublished - Feb 1 2005

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Keywords

  • Interleukin-10
  • Lipopolysaccharide
  • Lung
  • Neutrophils
  • Protein kinases
  • Transgenic/knockout

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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