Impact of IL-10 on diaphragmatic cytokine expression and contractility during Pseudomonas Infection.
Severe weakness of the respiratory muscles, with attendant respiratory failure and death, has been documented in sepsis. In this study, we show that during murine pulmonary infection with Pseudomonas aeruginosa, multiple proinflammatory genes are up-regulated not only within the lungs, but also within the diaphragm. Significant induction of TNF-alpha, IL-1alpha, IL-1beta, IL-6, and IL-18 gene expression occurred within the diaphragm in a bacterial dose-dependent manner. We determined whether the anti-inflammatory cytokine IL-10 could blunt proinflammatory gene expression within the diaphragm under these conditions. The IL-10 receptor was found to be expressed by the diaphragm in vivo as well as in primary diaphragmatic muscle cell cultures. Transduction of myoblasts with an adenoviral vector (Ad-IL-10) induced strong IL-10 expression, and intramuscular injection of the same vector in vivo produced significant increases in IL-10 serum levels. Ad-IL-10 treatment of mice infected with P. aeruginosa significantly inhibited the induction of proinflammatory cytokines within the diaphragm, but not in the infected lungs. Ad-IL-10 treatment also led to greatly improved diaphragmatic force production in infected mice. These results suggest that pulmonary infection triggers proinflammatory gene expression by the diaphragm along with diaphragmatic weakness. Shifting the balance between pro- and anti-inflammatory mediators in favor of the latter by IL-10 gene delivery was able to restore normal diaphragmatic force-generating capacity under these conditions, suggesting a possible avenue for therapeutic intervention.
Divangahi
Maziar
M
Respiratory Division, Room L411, Royal Victoria Hospital, 687 Pine Ave. West, Montreal, PQ, Canada.
Demoule
Alexandre
A
Danialou
Gawiyou
G
Yahiaoui
Linda
L
Bao
Weisheng
W
Xing
Zhou
Z
Petrof
Basil J
BJ
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D003964:Diaphragm / Q000276:immunology* / Q000382:microbiology / Q000503:physiopathology; D007249:Inflammation / Q000276:immunology / Q000382:microbiology; D016753:Interleukin-10 / Q000502:physiology*; D008171:Lung Diseases / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction; D011552:Pseudomonas Infections / Q000276:immunology*; D053701:Receptors, Interleukin-10 / Q000378:metabolism; D014161:Transduction, Genetic; D015854:Up-Regulation
D016207:Cytokines; D053701:Receptors, Interleukin-10; D016753:Interleukin-10