title: Interleukin 10 extends the effectiveness of standard therapy during late sepsis with serum interleukin 6 levels predicting outcome.
abstract: Patients with septic shock often display features of T cell hyporesponsiveness and immune suppression, which, if persistent, are associated with increased mortality. In the murine cecal ligation and puncture (CLP) model of sepsis, we previously reported that early treatment with the anti-inflammatory cytokine interleukin 10 (IL-10) delays the onset of irreversible shock, defined as the time at which rescue surgery to remove the necrotic cecum is no longer effective. Because IL-10 can be immunostimulatory for T cells, we hypothesized that in the CLP model, late IL-10 treatment after removal of the infectious nidus at the onset of irreversible shock would restore T cell responsiveness and increase survival. C57BL/6J mice were subjected to lethal CLP with and without rescue surgery, concurrent with IL-10 treatment, at the onset of irreversible shock. Survival and serum IL-6 levels were measured as markers of the response to treatment. Ten hours after intervention, all groups exhibited T cell hyporesponsiveness marked by impaired interferon (IFN)-gamma production by Con A-stimulated splenocytes. IL-6 levels at 10 h were related to outcome independent of treatment. By 25 h after intervention, only the dual treatment group of cecal removal and IL-10 exhibited T cell responsiveness that was similar to pre-CLP levels (P = 0.26) and had a 7-day survival of 90% (P < or = 0.002 compared with all other groups). Thus, even in the advanced stages of septic shock when standard therapies fail, treatment with IL-10 extends the therapeutic window. For an individual mouse, the efficacy of such treatment may be predicted by an early postintervention IL-6 level.
authors.affiliation: Department of Medicine, Division of Pediatric Pharmacology and Critical Care Medicine, Rainbow Babies and Children's Hospital and Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: Mollie O
authors.initials: MO
authors.lastname: Manley
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: O'Riordan
authors.forename: Alan D
authors.initials: AD
authors.lastname: Levine
authors.forename: Samir Q
authors.initials: SQ
authors.lastname: Latifi
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism / Q000502:physiology* / Q000627:therapeutic use; D015850:Interleukin-6 / Q000097:blood* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000627:therapeutic use; D018805:Sepsis; D012772:Shock, Septic / Q000628:therapy*; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D015850:Interleukin-6; D011994:Recombinant Proteins; D016753:Interleukin-10; D007371:Interferon-gamma