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This Article Full Text Full Text (PDF) All Versions of this Article: 288/2/L251    most recent 00122.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Spight, D. Articles by Shanley, T. P. Search for Related Content PubMed PubMed Citation Articles by Spight, D. Articles by Shanley, T. P.

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

Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, and the Cincinnati Children’s Hospital Research Foundation, Cincinnati, Ohio

Submitted 1 April 2004 ; accepted in final form 25 September 2004

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-B. IL-10 has been previously identified as an important endogenous anti-inflammatory cytokine in vivo on the basis of inhibiting NF-B activation; however, the mechanism of this inhibition remains incompletely defined. We hypothesized that IL-10 regulated NF-B activation in vivo via IK 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 IK 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.

interleukin-10; transgenic/knockout; lung; protein kinases; neutrophils; lipopolysaccharide