Immunoregulatory effects of regulated, lung-targeted expression of IL-10 in vivo.
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-kappaB. IL-10 has been previously identified as an important endogenous anti-inflammatory cytokine in vivo on the basis of inhibiting NF-kappaB activation; however, the mechanism of this inhibition remains incompletely defined. We hypothesized that IL-10 regulated NF-kappaB activation in vivo via IkappaK 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 IkappaK 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.
Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229-3039, USA.
Donn
D
Spight
Bin
B
Zhao
Michael
M
Haas
Susan
S
Wert
Alvin
A
Denenberg
Thomas P
TP
Shanley
D000818:Animals; D018925:Chemokines / Q000378:metabolism; D004334:Drug Administration Schedule; D018390:Gene Targeting; D006801:Humans; D007107:Immune System / Q000187:drug effects* / Q000502:physiology*; D016753:Interleukin-10 / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000276:immunology* / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000187:drug effects; D010641:Phenotype
D018925:Chemokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D016753:Interleukin-10