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.

Role of nitric oxide in acute lung inflammation: lessons learned from the inducible nitric oxide synthase knockout mouse.

OBJECTIVE: Acute lung inflammation is characterized by complex interactions among cytokines, chemokines, adhesion molecules, leukocytes, and other mediators. Proinflammatory cytokines have been implicated in the up-regulation of the inducible form of nitric oxide synthase (iNOS), which produces large amounts of nitric oxide (NO). Conversely, in some systems, NO regulates the expression of cytokines to affect leukocyte recruitment. Thus, the role of NO both exogenously administered and endogenously produced by iNOS in acute lung inflammation has not been fully elucidated. The current studies suggest a proinflammatory role for inhaled NO in a compartmentalized model of lung injury, whereas blocking of iNOS afforded protection. These results and other previous investigations have been complicated by the use of nonselective blockers of the iNOS isoform. MEASUREMENTS AND MAIN RESULTS: In an attempt to circumvent this, we examined the response of the lung to direct endotoxin challenge in mice in which iNOS had been genetically deleted (iNOS-/-). We observed a significant decrease in the inflammatory response in the iNOS-/- mice compared with wild-type mice as characterized by decreases in neutrophil accumulation and cytokine expression. Additionally, the lung cytokine response in the iNOS-/- mice was characterized by a significant increase in interleukin-12 and an inability to up-regulate interleukin-10. CONCLUSIONS: Induction of NO may be a key mediator in driving the cytokine response to endotoxin toward an increased type-2 (interleukin-10) response and a diminished type-1 (interleukin-12) response.