Ulinastatin mediates suppression of regulatory T cells through TLR4/NF-κB signaling pathway in murine sepsis

Cao, Chao; Yin, Chengfen; Chai, Yifeng; Jin, Heng; Wang, Lijun; Shou, Songtao

doi:10.1016/j.intimp.2018.09.025

Cited by 26 publications

(15 citation statements)

References 43 publications

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“…TLR4 and MyD88 were overexpressed in RAW264.7 cells respectively ( 38 , 39 ). In brief, when the RAW264.7 cells reached 60% confluence, they were transfected with pcDNA3-TLR4-YFP plasmid DNA (Addgene, Cambridge, MA, USA) and pcDNA3-Myd88-CFP plasmid DNA (Addgene, Cambridge, MA, USA) using Lipofectamine 3000 Reagent (Invitrogen Life Technologies, CA, USA) following the manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

Inhibitory Effects of the Lactobacillus rhamnosus GG Effector Protein HM0539 on Inflammatory Response Through the TLR4/MyD88/NF-кB Axis

Yang

Lun

et al. 2020

Front. Immunol.

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Inflammatory bowel disease (IBD) is a chronic and relapsing intestinal inflammatory condition with no effective treatment. Probiotics have gained wide attention because of their outstanding advantages in intestinal health issues. In previous studies, a novel soluble protein, HM0539, which is derived from Lactobacillus rhamnosus GG (LGG), showed significant protective effects against murine colitis, but no clear precise mechanism for this effect was provided. In this study, we hypothesized that the protective function of HM0539 might be derived from its modulation of the TLR4/Myd88/NF-κB axis signaling pathway, which is a critical pathway widely involved in the modulation of inflammatory responses. To test this hypothesis, the underlying anti-inflammatory effects and associated mechanisms of HM0539 were determined both in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and in dextran sulfate sodium (DSS)-induced murine colitis. Our results showed that HM0539 inhibited the expression of cyclooxygenase-2 (COX-2) and the expression inducible nitric oxide synthase (iNOS) by down-regulating the activation of their respective promoter, and as a result this inhibited the production of prostaglandin E2 (PGE2) and nitric oxide (NO). Meanwhile, we demonstrated that HM0539 could ultimately modulate the activation of distal NF-κB by reducing the activation of TLR4 and suppressing the transduction of MyD88. However, even though the overexpression of TLR4 or MyD88 obviously reversed the effect of HM0539 on LPS-induced inflammation, HM0539 still retained some anti-inflammatory activity. Consistent with the in vitro findings, we found that HM0539 inhibited to a great extent the production of inflammatory mediators associated with the suppression of the TLR4/Myd88/NF-κB axis activation in colon tissue. In conclusion, HM0539 was shown to be a promising anti-inflammatory agent, at least in part through its down-regulation of the TLR4-MyD88 axis as well as of the downstream MyD88-dependent activated NF-κB signaling, and hence might be considered as a potential therapeutic option for IBD.

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Section: Methodsmentioning

confidence: 99%

Inhibitory Effects of the Lactobacillus rhamnosus GG Effector Protein HM0539 on Inflammatory Response Through the TLR4/MyD88/NF-кB Axis

Yang

Lun

et al. 2020

Front. Immunol.

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“…Increased Treg cell population would prevent recovery of the immune system from excessive immune responses. Importantly, these resistant effects are possibly due to TLR4 deficiency and associated NF-κB signal pathways 188 .…”

Section: Apoptosis-induced Lymphopenia During Sepsismentioning

confidence: 99%

Pathological alteration and therapeutic implications of sepsis-induced immune cell apoptosis

2019

Self Cite

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Sepsis is a life-threatening organ dysfunction syndrome caused by dysregulated host response to infection that leads to uncontrolled inflammatory response followed by immunosuppression. However, despite the high mortality rate, no specific treatment modality or drugs with high efficacy is available for sepsis to date. Although improved treatment strategies have increased the survival rate during the initial state of excessive inflammatory response, recent trends in sepsis show that mortality occurs at a period of continuous immunosuppressive state in which patients succumb to secondary infections within a few weeks or months due to post-sepsis “immune paralysis.” Immune cell alteration induced by uncontrolled apoptosis has been considered a major cause of significant immunosuppression. Particularly, apoptosis of lymphocytes, including innate immune cells and adaptive immune cells, is associated with a higher risk of secondary infections and poor outcomes. Multiple postmortem studies have confirmed that sepsis-induced immune cell apoptosis occurs in all age groups, including neonates, pediatric, and adult patients, and it is considered to be a primary contributing factor to the immunosuppressive pathophysiology of sepsis. Therapeutic perspectives targeting apoptosis through various strategies could improve survival in sepsis. In this review article, we will focus on describing the major apoptosis process of immune cells with respect to physiologic and molecular mechanisms. Further, advances in apoptosis-targeted treatment modalities for sepsis will also be discussed.

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“…UTI inhibits intensive production of proinflammatory mediators such as IL-8, TNF-α. [19][20][21] Early administration of UTI has been demonstrated to inhibit neutrophil protease release and excessive inflammatory responses and reduce the release of oxygen free radicals and consumption of superoxide dismutase. 22,23 Also, UTI can inhibited fibrosis formation in kidney and lungs.…”

Section: Discussionmentioning

confidence: 99%

Ulinastatin prevents hyperoxia-induced lung injury on newborn rats by downregulating TNF-α and inhibiting macrophage infiltration

Fang

Deng

Kong

2018

Preprint

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Ulinastatin (UTI) can support protection for several organs through inhibition of the release of inflammatory factors, absorbing oxygen radicals, and inhibition the progression of fibrosis. However, whether UTI has effect on hyperoxia-induced lung injury is still unclear. In this study, the effects of UTI treatment on newborn rats suffering hyperoxia-induced lung injury were examined. The results demonstrated that UTI treatment significantly attenuated the wet/dry weight ratio, downregulated the levels of tumor necrosis factor-α (TNF-α), inhibited macrophage infiltration, and improved the average weight of rats. The most significant changes were observed in high-dose UTI treatment group. However, UTI had no effect on pulmonary superoxide dismutase (SOD) and malondialdehyde (MDA) levels. Our results suggested that Ulinastatin prevents hyperoxia-induced lung injury on newborn rats by downregulating TNF-α and inhibiting macrophage infiltration.

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Ulinastatin mediates suppression of regulatory T cells through TLR4/NF-κB signaling pathway in murine sepsis

Cited by 26 publications

References 43 publications

Inhibitory Effects of the Lactobacillus rhamnosus GG Effector Protein HM0539 on Inflammatory Response Through the TLR4/MyD88/NF-кB Axis

Inhibitory Effects of the Lactobacillus rhamnosus GG Effector Protein HM0539 on Inflammatory Response Through the TLR4/MyD88/NF-кB Axis

Pathological alteration and therapeutic implications of sepsis-induced immune cell apoptosis

Ulinastatin prevents hyperoxia-induced lung injury on newborn rats by downregulating TNF-α and inhibiting macrophage infiltration

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