title: PAI-1 and IFN-γ in the regulation of innate immune homeostasis during sublethal yersiniosis.
abstract: Plasminogen activator inhibitor type 1 (PAI-l), a key part of the fibrinolytic system, plays a critical host protective role during the acute phase of infection by regulating interferon(IFN)-γ release. IFN-γ regulates PAI-1 expression, which suggests an intricate interplay between PAI-1 and IFN-γ. Here, using the notion of a feedback loop, we report the complicated regulatory relationship between PAI-1 and IFN-γ. Mice were inoculated intravenously with 1×10(3) colony forming units of Yersinia enterocolitica; PAI-1 deficiency enhanced lethality (p<0.0001) and increased bacterial growth and dissemination (p=0.08 on day 3, p=0.004 on day 5, respectively). PAI-1 significantly increased the levels IFN-γ mRNA (p<0.005), which may increase survival and decrease bacterial burden. Simultaneously, we showed that IFN-γ increased PAI-1 mRNA levels in vivo (p<0.05). Next, we investigated the transduction signal pathway. After mice were inoculated intraperitoneally with 50μg lipopolysaccharide (LPS), both levels of IFN-γ mRNA (p=0.05) and levels of PAI-1 mRNA (p<0.0001) decreased in MyD88-deficient mice. The same trend was also found in mice treated with 1000μg LPS. As a result of correlations of IFN-γ and PAI-1 in wild-type mice, we delineated the transduction signal pathway, namely MyD88-IFN-γ-PAI-1. The in vivo LPS-injected animal model further confirmed that PAI-1 feedback controlled IFN-γ in a direct or indirect manner. New perspectives of the relationship between PAI-1 and IFN-γ should help in understanding the complex and often conflicting results that have been reported in different infection models. Thus, the feedback loop between PAI-1 and IFN-γ is part of the dynamic equilibrium of coagulation and inflammation that helps maintain innate immune homeostasis.
authors.affiliation: Department of Pediatric Surgery, General Hospital of PLA, Beijing 100853, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhao
authors.forename: Yuxia
authors.initials: Y
authors.lastname: Han
authors.forename: Dongxia
authors.initials: D
authors.lastname: Zhang
authors.forename: Liangyan
authors.initials: L
authors.lastname: Zhang
authors.forename: Deyan
authors.initials: D
authors.lastname: Luo
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics* / Q000378:metabolism; D015009:Yersinia Infections / Q000235:genetics* / Q000276:immunology* / Q000382:microbiology / Q000401:mortality; D015008:Yersinia enterocolitica
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D007371:Interferon-gamma