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Effect of IL-10 on Neutrophil Recruitment and Survival after Pseudomonas aeruginosa Challenge

¹ Division of Critical Care Medicine, Department of Pediatrics and Communicable Diseases; ² Department of Pathology and ³ Pulmonary and Critical Care Medicine, Department of Medicine, University of Michigan Medical School, Ann Arbor, Michigan

Correspondence and requests for reprints should be addressed to Thomas P. Shanley, M.D., 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. E-mail: tshanley{at}med.umich.edu

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-) 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- 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.

Key Words: IL-10 • Pseudomonas • neutrophils • chemokines

CLINICAL RELEVANCE This work provides insight on how counterregulatory molecules have dual effects on regulation, inflammation, and subsequent pathogen clearance. When they are not properly regulated, the consequences can be equally as detrimental as dysregulated proinflammation.