Diminished bacterial clearance is associated with decreased IL-12 and interferon-gamma production but a sustained proinflammatory response in a murine model of postseptic immunosuppression

Abstract

After a major illness or injury, immune status in critically ill patients may fluctuate between a marked proinflammatory response and an immunosuppressed state. Postinflammatory immunosuppression can result in increased susceptibility to infection. Alterations of cytokine production, such as suppression of IFNgamma and elevation of the anti-inflammatory cytokine IL-10, are believed to contribute to postinflammatory immunosuppression. We examined antimicrobial immunity in mice that had previously been subjected to a sublethal cecal ligation and puncture (CLP) as a model of major injury. Mice were challenged with Pseudomonas aeruginosa (5 x 10(7) CFU i.v.) on day 5 after CLP or sham surgery. Bacterial clearance in mice after CLP was impaired and associated with decreased production of IFNgamma and increased production of IL-10 in the early response to the Pseudomonas challenge. Pseudomonas-induced production of the IFNgamma-inducing factor IL-12 was also decreased in post-CLP mice. However, splenocytes from post-CLP mice remained responsive to exogenous stimulation with the IFNgamma-inducing cytokines IL-12, IL-15, and IL-18 as well as T-cell receptor activation. Furthermore, production of the proinflammatory cytokines TNF-alpha, IL-1beta, and IL-6 were as high, or higher, in the post-CLP group compared with sham mice after P. aeruginosa challenge. Blockade of IL-10 did not reverse IL-12 and IFNgamma suppression in splenocytes from post-CLP mice. These studies show that suppressed bacterial clearance in post-CLP mice is associated with decreased production of IFNgamma and IL-12 and with increased production of IL-10 and proinflammatory cytokines.