The role of interferon-γ in the pathogenesis of acute intra-abdominal sepsis

Abstract

Several studies indicate that IFN-γ facilitates systemic inflammation during endotoxin-induced shock. However, the pathobiology of IFN-γ in clinically relevant models of septic shock, such as CLP, is not well understood. In this study, the role of IFN-γ in the pathogenesis of CLP-induced septic shock was evaluated by examining IFN-γ production at the tissue and cellular levels. The impact of IFN-γ neutralization on systemic inflammation, bacterial clearance, and survival was also determined. Following CLP, concentrations of IFN-γ in plasma and peritoneal lavage fluid were low in comparison with concentrations of IL-6 and MIP-2, as was IFN-γ mRNA expression in liver and spleen. The overall percentage of IFN-γ+ splenocytes was <5% after CLP and not statistically different from control mice. Intracellular IFN-γ was present in a large proportion of peritoneal exudate cells after CLP, primarily in infiltrating myeloid cells and NK cells. i.p. myeloid cell activation was decreased in IFN-γKO mice, and plasma concentrations of IL-6 and MIP-2 were significantly lower in IFN-γKO mice and in mice treated with anti-IFN-γ compared with controls, but bacterial clearance was not affected. IFN-γKO mice were resistant to CLP-induced mortality when treated with systemic antibiotics. However, neutralization of IFN-γ with blocking antibodies did not improve survival significantly. These studies show that IFN-γ facilitates the proinflammatory response during CLP-induced septic shock. However, neutralization of IFN-γ did not improve survival uniformly.

Natural Killer (NK) Cells in Antibacterial Innate Immunity: Angels or Devils?

“…This deleterious effect was also shown in the CLP model of polymicrobial peritonitis (92) and in a CLP model followed by a P. aeruginosa infection (93). Polymicrobial peritonitis performed in IFN-γ receptor-deficient mice (94) or in rats given anti-IFN-γ antibodies (95) led to the similar demonstration of this negative role. In mice injected with LPS, the ambiguous role of IFN-γ was demonstrated: IFN-γ protected against LPSinduced lung edema but acted in synergy with LPS to enhance the occurrence of death (96).…”

SOCS1 is a negative regulator of metabolic reprogramming during sepsis

“…Several studies have shown that the physiopathology observed in SOCS1-knockout mice depends on IFN-γ production (30)(31)(32). Additionally, IFN-γ plays a detrimental role in polymicrobial sepsis (33). Therefore, we evaluated whether pharmacological inhibition of SOCS1 would lead to elevated levels of IFN-γ.…”

NK cells require IL-28R for optimal in vivo activity

“…Serum cytokines were also assessed in the same mice to correlate the strength of the systemic inflammatory responses. Six hours after LPS challenge, cytokines characteristic of lethal endotoxicosis (32), such as IFN-γ, were decreased in mice deficient for IFNAR1 or IL-28R. The early TNF-α signal was significantly decreased in IFNAR1 −/− mice only whereas no differences were found in serum KC levels between WT and IL-28R…”

“…To address whether the absence of IFN-λ signaling also regulated systemic polymicrobial sepsis and septic shock, a cecal ligation and puncture (CLP) model was performed as previously described (33). Because lethality was shown to be dependent upon NK cell IFN-γ production (32,34,35), not surprisingly the IL-28R −/− mice were relatively resistant compared with WT mice (Fig. 3A).…”