Prolonged inflammatory response to acute Pseudomonas challenge in interleukin-10 knockout mice.
Cystic fibrosis (CF) lung disease is characterized by a neutrophilic infiltrate that is excessive relative to the burden of infection. Decreased interleukin-10 in CF airways may impair proper termination of inflammation, leading to persistence of neutrophils after acute infections have been cleared. This could explain reports of lung inflammation in the absence of bacteria in infants with CF. We evaluated the kinetics of inflammation after transient Pseudomonas aeruginosa challenge in IL-10 knockout (KO) and wild-type (WT) mice. Both types of mice cleared the infection by Day 6 (p > or = 0.29). However, IL-10 KO mice had more neutrophils in bronchoalveolar lavage fluid than did WT mice on Days 4 (p < 0.0001), 6 (p < 0.0001), and 8 (p = 0.042). IL-10 KO mice had high concentrations of proinflammatory cytokines in BAL on Days 2 and 4, with some cytokines detectable on Days 6 and 8, whereas cytokines in BAL from WT mice were greatest on Day 2 and undetectable by Day 4. Moreover, IL-10 KO mice failed to regenerate IkappaBalpha once degraded and subsequently had prolonged activation of NF-kappaB. These data suggest that IL-10 deficiency contributes to prolonged inflammatory responses early in CF, when infection may be transient.
Chmiel
James F
JF
Department of Pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA. jxc34@po.cwru.edu
Konstan
Michael W
MW
Saadane
Aicha
A
Krenicky
Jeanne E
JE
Lester Kirchner
H
H
Berger
Melvin
M
D000208:Acute Disease; D000818:Animals; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002452:Cell Count; D015169:Colony Count, Microbial; D003550:Cystic Fibrosis / Q000382:microbiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D020672:I-kappa B Proteins; D007249:Inflammation; D018836:Inflammation Mediators / Q000378:metabolism*; D016753:Interleukin-10 / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000473:pathology; D011552:Pseudomonas Infections / Q000150:complications / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D011550:Pseudomonas aeruginosa / Q000302:isolation & purification; D012141:Respiratory Tract Infections / Q000150:complications / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D016753:Interleukin-10; D000072000:NF-KappaB Inhibitor alpha