IFN-  is a master regulator of endotoxin shock syndrome in mice primed with heat-killed Propionibacterium acnes

Abstract

Hyper-coagulation, hypothermia, systemic inflammatory responses and shock are major clinical manifestations of endotoxin shock syndrome in human. As previously reported, mice primed with heat-killed Propionibacterium acnes are highly susceptible to the action of LPS to induce tumour necrosis factor (TNF)-alpha and to that of TNF-alpha to trigger lethal shock. Here we investigated the mechanisms underlying the P. acnes-induced sensitization to LPS and TNF-alpha and the development of individual symptoms after subsequent challenge with LPS or TNF-alpha. Propionibacterium acnes-primed wild-type (WT) mice, but not naive mice, exhibited hyper-coagulation with elevated levels of thrombin-antithrombin complexes and anti-fibrinolytic plasminogen activator inhibitor 1 in their plasma, hypothermia, systemic inflammatory responses and high mortality rate after LPS or TNF-alpha challenge. Propionibacterium acnes treatment reportedly induces both T(h)1 and T(h)17 cell development. Propionibacterium acnes-primed Il12p40(-/-) and Ifngamma(-/-) mice, while not Il17A(-/-) mice, evaded all these symptoms/signs upon LPS or TNF-alpha challenge, indicating essential requirement of IL-12-IFN-gamma axis for the sensitization to LPS and TNF-alpha. Furthermore, IFN-gamma blockade just before LPS challenge could prevent P. acnes-primed WT mice from endotoxin shock syndrome. These results demonstrated requirement of IFN-gamma to the development of endotoxin shock and suggested it as a potent therapeutic target for the treatment of septic shock.

Curcumin attenuated acute Propionibacterium acnes -induced liver injury through inhibition of HMGB1 expression in mice

“…acnes-induced liver injury is associated with over production of various cytotoxic factors against the hepatocyte. Among these, TNF-α and IFN-γ are crucial mediators in P. acnes-induced inflammation and granuloma formation [33][34][35]. In the present study, we found that curcumin can effectively reduce P. acnes-induced TNF-α and IFN-γ expression in vivo.…”

Importance of Kupffer Cells in the Development of Acute Liver Injuries in Mice

“…The morbidity and mortality of P. acnes -primed mice after challenge with a subclinical dose of LPS were demonstrated. After the LPS challenge, the P. acnes -primed mice developed proinflammatory cytokinemia, systemic hypercoagulation, and hypothermia, followed by a high mortality [18]. All these signs were observed in severe septic patients [19,20].…”

Arid5a exacerbates IFN-γ–mediated septic shock by stabilizing T-bet mRNA

“…), or IFN-γ are highly resistant to P. acnes-primed, LPS-induced septic shock (15). Thus, it is believed that the P. acnes-primed endotoxic shock mouse model is T-cellmediated and IFN-γ-dependent.…”

“…Thus, it is believed that the P. acnes-primed endotoxic shock mouse model is T-cellmediated and IFN-γ-dependent. Previously, it was proposed that priming mice with heat-killed P. acnes results in the induction of IL-12 by macrophages, which causes increased IFN-γ production by Th1 cells and primes the macrophages to be susceptible to LPS (15). Thus, to evaluate whether the regulation of IFN-γ expression in Th1 cells by Arid5a affects endotoxic shock in mice, we challenged WT and Arid5a-deficient mice with P. acnes for 5 d, followed by a sublethal dose of LPS (Fig.…”