IL-12, but Not IL-18, Is Critical to Neutrophil Activation and Resistance to Polymicrobial Sepsis Induced by Cecal Ligation and Puncture

Abstract

Sepsis is a systemic inflammatory response resulting from local infection due, at least in part, to impaired neutrophil migration. IL-12 and IL-18 play an important role in neutrophil migration. We have investigated the mechanism and relative role of IL-12 and IL-18 in polymicrobial sepsis induced by cecal ligation and puncture (CLP) in mice. Wild-type (WT) and IL-18−/− mice were resistant to sublethal CLP (SL-CLP) sepsis. In contrast, IL-12−/− mice were susceptible to SL-CLP sepsis with high bacteria load in peritoneal cavity and systemic inflammation (serum TNF-α and lung neutrophil infiltration). The magnitude of these events was similar to those observed in WT mice with lethal CLP sepsis. The inability of IL-12−/− mice to restrict the infection was not due to impairment of neutrophil migration, but correlated with decrease of phagocytosis, NO production, and microbicidal activities of their neutrophils, and with reduction of systemic IFN-γ synthesis. Consistent with this observation, IFN-γ−/− mice were as susceptible to SL-CLP as IL-12−/− mice. Moreover, addition of IFN-γ to cultures of neutrophils from IL-12−/− mice restored their phagocytic, microbicidal activities and NO production. Mortality of IL-12−/− mice to SL-CLP was prevented by treatment with IFN-γ. Thus we show that IL-12, but not IL-18, is critical to an efficient host defense in polymicrobial sepsis. IL-12 acts through induction of IFN-γ and stimulation of phagocytic and microbicidal activities of neutrophils, rather than neutrophil migration per se. Our data therefore provide further insight into the defense mechanism against this critical area of infectious disease.

Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18

“…1A), indicating that endogenous IL-18 plays a critical adverse role in neonatal sepsis. This finding in neonates is in stark contrast to the absence of any effect of IL-18 deletion alone in adults after polymicrobial sepsis induced by cecal ligation and puncture (CLP) (12). Of note, sepsis modeling using cecal slurry (CS) results in a much more robust early systemic inflammatory response than seen with CLP; this robust response may contribute to the differences in survival seen between IL-18 −/− neonates and adults (13).…”

The CD4+ T Cell-Mediated IFN-γ Response to Helicobacter Infection Is Essential for Clearance and Determines Gastric Cancer Risk

“…Although being dispensable for the recruitment of neutrophils in our as well as other model systems (65), IFN-␥ is known to induce neutrophil phagocytosis (66), microbicidal activity (67), and survival (68). We propose that CD4 ϩ T cell-derived IFN-␥ must act locally on neutrophils to activate their anti-Helicobacter properties.…”

Targeting IL-12/IL-23 by Employing a p40 Peptide-Based Vaccine Ameliorates TNBS-Induced Acute and Chronic Murine Colitis

“…IL-12 has been demonstrated to be chemotactic for neutrophils and NK cells through induction of synthesis of platelet-activating factor (44,45). It also has been reported that IL-12 is critical to neutrophil activation and resistance to polymicrobial sepsis induced by cecal ligation and puncture (46). Therefore, vaccine-induced specific antibodies blocked the biophysical functions of IL-12, leading to less migration and activation of neutrophils to the local colon tissue and, thus, ameliorating intestinal inflammation.…”