Effect of IL-10 on neutrophil recruitment and survival after Pseudomonas aeruginosa challenge.
IL-10 is a potent, endogenous anti-inflammatory cytokine known to decrease cytokine and keratinocyte-derived chemokine (KC) expression. Traditionally, in vivo effects of IL-10 were extrapolated from studies employing systemic antibody neutralization. As a result, divergent data regarding the protective and/or harmful roles of IL-10 have been reported. In this study, we used a lung-specific, tetracycline-inducible IL-10 overexpression-transgenic (IL-10 OE) mouse to study the effects of IL-10 overexpression on Pseudomonas aeruginosa-induced lung inflammation and corresponding survival in mice. Overexpression of IL-10 in the lung significantly increased mortality. During the early phase after infection (6-hours after infection), neutrophil recruitment as well as cytokine (TNF-alpha) and chemokine (KC) expression were significantly decreased in the IL-10 OE mice, which resulted in attenuated bacterial clearance. In contrast, overzealous production of KC and TNF-alpha intensified neutrophil infiltration and increased vascular leakage in IL-10 OE mice at the later stage of infection (24 hours after infection). Neutrophil depletion showed impaired bacterial clearance in both control and IL-10 OE mice, and further enhanced mouse mortality, whereas exogenous administration of KC reversed this finding. Our data indicate that early neutrophil recruitment is important for combating bacterial infection, and that the inhibition of neutrophil recruitment by IL-10 results in insufficient bacteria clearance in the lung, leading to excessive development of inflammation and increased mortality.
Sun
Lei
L
Division of Critical Care Medicine, Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, 109 Zina Pitcher Place, 4460 BSRB, Ann Arbor, MI 48109, USA.
Guo
Ren-Feng
RF
Newstead
Michael W
MW
Standiford
Theodore J
TJ
Macariola
Demetrio R
DR
Shanley
Thomas P
TP
D000818:Animals; D002199:Capillary Permeability; D018925:Chemokines / Q000378:metabolism; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000098:blood supply / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008822:Mice, Transgenic; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology*; D018410:Pneumonia, Bacterial / Q000276:immunology* / Q000382:microbiology; D011552:Pseudomonas Infections / Q000276:immunology* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018925:Chemokines; C508609:IL10 protein, human; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C074302:keratinocyte-derived chemokines