scholarly journals Accelerated Tryptophan Degradation Predicts Poor Survival in Trauma and Sepsis Patients

2010 ◽  
Vol 3 ◽  
pp. IJTR.S3983 ◽  
Author(s):  
Martin Ploder ◽  
Andreas Spittler ◽  
Katharina Kurz ◽  
Gabriele Neurauter ◽  
Linda E. Pelinka ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Immune Activation ◽  
Tryptophan Degradation ◽  
Immune System Activation ◽  
Tnf Α ◽  
In Vitro Response ◽  
Immune Activation Marker ◽  
Factor Α

Immune system activation and inflammation accompanies immune dysfunction in trauma and sepsis patients. Immunodeficiency may develop in such patients as one consequence of an activated chronic pro-inflammatory response. According to recent data, degradation of L-tryptophan (TRP) via the kynurenine (KYN) pathway by the cytokine-inducible enzyme indoleamine 2,3-dioxygenase (IDO) could represent an important contributor to the deficient responsiveness of immunocompetent cells. Compared to healthy controls, patients post trauma or with sepsis had increasing KYN concentrations and KYN to TRP ratios (KYN/TRP) whereas TRP concentrations decreased. Likewise, concentrations of cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and of immune activation marker neopterin increased in patients (all p < 0.001). Furthermore in patients KYN/TRP, KYN and neopterin concentrations were further increasing (all p < 0.001), whereas the changes of TRP, TNF-α and IL-6 concentrations were not significant. Compared to the survivors, the non-survivors had a higher concentration of KYN, neopterin, TNF-α and IL-6 as well as a higher KYN/TRP ratio. KYN/TRP correlated with neopterin (p < 0.001) and also with TNF-α (p < 0.01) and IL-6 concentrations (p < 0.05) and inversely with the in vitro response of stimulated monocytes. We conclude that increased TRP degradation in patients post trauma is closely associated with immune activation. Cytokines released during the pro-inflammatory response may induce the activity of IDO and thus accelerate TRP degradation. Thus, increased IDO activity most likely represents a result of host response to pro-inflammation in patients. Data support a possible role of inflammation-induced IDO in the diminished immunoresponsiveness in patients.

Accelerated Tryptophan Degradation in Trauma and Sepsis Patients is Related to Pro-inflammatory Response and to the Diminished in vitro Response of Monocytes

Pteridines ◽  
2009 ◽  
Vol 20 (1) ◽  
pp. 54-61 ◽  
Author(s):  
Martin Ploder ◽  
Andreas Spittler ◽  
Katharina Schroecksnadel ◽  
Gabriele Neurauter ◽  
Linda E. Pelinka ◽  
...  
Keyword(s):  
Kynurenine Pathway ◽  
Tryptophan Degradation ◽  
Immune System Activation ◽  
Tnf Α ◽  
In Vitro Response ◽  
System Activation ◽  
Factor Α

Abstract Immune system activation and inflammation accompanies immune dysfunction in trauma and sepsis patients. Tryptophan degradation via the kynurenine pathway by the cytokine-inducible enzyme indoleamine 2,3-dioxygenase (IDO) could contribute to the deficient responsiveness of immunocompetent cells. Activated IDO in patients after trauma and with sepsis is indicated by an increased kynurenine to tryptophan ratio (kyn/trp), which was found to be associated with poor outcome of patients. In this study, tryptophan and kynurenine concentrations in 18 patients post trauma or with sepsis during 12-14 days of follow up (up to 84 specimens were available) were compared to concentrations of neopterin and cytokines tumor necrosis factor-α (TNF-α) and interleukin- 6 (IL-6) and the in vitro response of lipopolysaccharide-stimulated monocytes. Compared to healthy controls, average kyn/trp and kynurenine, TNF-α, IL-6 and neopterin concentrations were increased in patients, and tryptophan concentrations were decreased. During follow-up, only kyn/trp, kynurenine and neopterin concentrations (all p <0.001) were increasing, whereas the changes of tryptophan, TNF-α and IL-6 concentrations were not significant. Non-survivors presented not only with higher kyn/trp and with higher kynurenine and neopterin concentrations than survivors, but also TNF-α and IL-6 concentrations were higher. Kyn/trp correlated with neopterin (rs = 0.590; p <0.001) and also with TNF-α (rs = 0.374; p <0.01) and IL-6 concentrations (rs = 0.262; p <0.05) and inversely with the in vitro response of stimulated monocytes. Data imply that increased tryptophan degradation in patients post trauma is due to IDO activation. Increased IDO activity most likely represents a result of host defence response in patients, and data support a possible role of IDO to diminish immunoresponsiveness in such patients.

scholarly journals MiR-22-3p suppresses sepsis-induced acute kidney injury by targeting PTEN

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Xudong Wang ◽  
Yali Wang ◽  
Mingjian Kong ◽  
Jianping Yang
Keyword(s):  
Acute Kidney Injury ◽  
Inflammatory Response ◽  
Periodic Acid ◽  
Kidney Injury ◽  
Luciferase Reporter ◽  
Tunel Staining ◽  
Tnf Α

Abstract Background: Septic acute kidney injury is considered as a severe and frequent complication that occurs during sepsis. The present study was performed to understand the role of miR-22-3p and its underlying mechanism in sepsis-induced acute kidney injury. Methods: Rats were injected with adenovirus carrying miR-22-3p or miR-NC in the caudal vein before cecal ligation. Meanwhile, HK-2 cells were transfected with the above adenovirus following LPS stimulation. We measured the markers of renal injury (blood urea nitrogen (BUN), serum creatinine (SCR)). Histological changes in kidney tissues were examined by hematoxylin and eosin (H&E), Masson staining, periodic acid Schiff staining and TUNEL staining. The levels of IL-1β, IL-6, TNF-α and NO were determined by ELISA assay. Using TargetScan prediction and luciferase reporter assay, we predicted and validated the association between PTEN and miR-22-3p. Results: Our data showed that miR-22-3p was significantly down-regulated in a rat model of sepsis-induced acute kidney injury, in vivo and LPS-induced sepsis model in HK-2 cells, in vitro. Overexpression of miR-22-3p remarkably suppressed the inflammatory response and apoptosis via down-regulating HMGB1, p-p65, TLR4 and pro-inflammatory factors (IL-1β, IL-6, TNF-α and NO), both in vivo and in vitro. Moreover, PTEN was identified as a target of miR-22-3p. Furthermore, PTEN knockdown augmented, while overexpression reversed the suppressive role of miR-22-3p in LPS-induced inflammatory response. Conclusions: Our results showed that miR-22-3p induced protective role in sepsis-induced acute kidney injury may rely on the repression of PTEN.

TNF-α and myocardial depression in endotoxemic rats: temporal discordance of an obligatory relationship

1998 ◽  
Vol 275 (2) ◽  
pp. R502-R508 ◽  
Author(s):  
Xianzhong Meng ◽  
Lihua Ao ◽  
Daniel R. Meldrum ◽  
Brian S. Cain ◽  
Brian D. Shames ◽  
...  
Keyword(s):  
Temporal Relationship ◽  
Contractile Function ◽  
Myocardial Depression ◽  
Tnf Α ◽  
Myocardial Contractile ◽  
Factor Α ◽  
Relationship Of

Exogenous tumor necrosis factor-α (TNF-α) induces delayed myocardial depression in vivo but promotes rapid myocardial depression in vitro. The temporal relationship between endogenous TNF-α and endotoxemic myocardial depression is unclear, and the role of TNF-α in this myocardial disorder remains controversial. Using a rat model of endotoxemia not complicated by shock, we sought to determine 1) the temporal relationship of changes in circulating and myocardial TNF-α with myocardial depression, 2) the influences of protein synthesis inhibition or immunosuppression on TNF-α production and myocardial depression, and 3) the influence of neutralization of TNF-α on myocardial depression. Rats were treated with lipopolysaccharide (LPS, 0.5 mg/kg ip). Circulating and myocardial TNF-α increased at 1 and 2 h, whereas myocardial contractility was depressed at 4 and 6 h. Pretreatment with cycloheximide or dexamethasone abolished the increase in circulating and myocardial TNF-α and preserved myocardial contractile function. Similarly, treatment with TNF binding protein immediately after LPS prevented myocardial depression. We conclude that endogenous TNF-α mediates delayed myocardial depression in endotoxemic rats and that inhibition of TNF-α production or neutralization of TNF-α preserves myocardial contractile function in endotoxemia.

scholarly journals Increments in cytokines and matrix metalloproteinases in skeletal muscle after injection of tissue-damaging toxins from the venom of the snakeBothrops asper

2002 ◽  
Vol 11 (2) ◽  
pp. 121-128 ◽  
Author(s):  
Alexandra Rucavado ◽  
Teresa Escalante ◽  
Catarina F. P. Teixeira ◽  
Cristina María Fernándes ◽  
Cecilia Díaz ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Inflammatory Response ◽  
Experimental Model ◽  
Peritoneal Macrophages ◽  
Interferon Γ ◽  
Local Inflammatory Response ◽  
Mmp Inhibitor ◽  
Tnf Α ◽  
Factor Α

Envenomations by the snakeBothrops asperare characterized by prominent local tissue damage (i.e. myonecrosis), blistering, hemorrhage and edema. Various phospholipases A2and metalloproteinases that induce local pathological alterations have been purified from this venom. Since these toxins induce a conspicuous inflammatory response, it has been hypothesized that inflammatory mediators may contribute to the local pathological alterations described. This study evaluated the local production of cytokines and matrix metalloproteinases (MMPs) as a consequence of intramuscular injections of an Asp-49 myotoxic phospholipase A2(myotoxin III (MT-III)) and a P-I type hemorrhagic metalloproteinase (BaP1) isolated fromB. aspervenom. Both enzymes induced prominent tissue alterations and conspicuous increments in interleukin (IL)-1β, IL-6 and a number of MMPs, especially gelatinase MMP-9, rapidly after injection. In contrast, no increments in tumor necrosis factor-α (TNF-α) and interferon-γ were detected. In agreement, MT-III and BaP1 did not induce the synthesis of TNF-α by resident peritoneal macrophagesin vitro. Despite the conspicuous expression of latent forms of MMPs in muscle, evidenced by zymography, there were no increments in activated MMP-2 and only a small increase in activated MMP-9, as detected by a functional enzymatic assay. This suggests that MMP activity was regulated by a highly controlled activation of latent forms and, probably, by a concomitant synthesis of MMP inhibitors. Since no hemorrhage nor dermonecrosis were observed after injection of MT-III, despite a prominent increase in MMP expression, and since inflammatory exudate did not enhance hemorrhage induced by BaP1, it is suggested that endogenous MMPs released in the tissue are not responsible for the dermonecrosis and hemorrhage characteristic ofB. asperenvenomation. Moreover, pretreatment of mice with the peptidomimetic MMP inhibitor batimastat did not reduce myotoxic nor edema-forming activities of MT-III, suggesting that MMPs do not play a prominent role in the pathogenesis of these effects in this experimental model. It is concluded that MT-III and BaP1 induce a local inflammatory response associated with the synthesis of IL-1β, IL-6 and MMPs. MMPs do not seem to play a prominent role in the acute local pathological alterations induced by these toxins in this experimental model.

Targeting Inflammatory Mediators: An Anticancer Mechanism of Thymoquinone Action

2020 ◽  
Vol 28 (1) ◽  
pp. 80-92
Author(s):  
Zakia Akter ◽  
Faiza Rafa Ahmed ◽  
Mousumi Tania ◽  
Md. Asaduzzaman Khan
Keyword(s):  
Cancer Development ◽  
Anticancer Activities ◽  
Inflammatory Pathways ◽  
Tnf Α ◽  
Anticancer Mechanism ◽  
Factor Α ◽  
Inflammatory Molecules

Background: : Thymoquinone is a promising anticancer molecule, the chemopreventive role of which is well-known at least in vitro and in the animal model. In this review article, we focused on the anti-inflammatory activities of thymoquinone in cancer cells. Method:: Research data on inflammation, cancer and thymoquinone were acquired from PubMed, Scopus, Web of Science and Google Scholar. We reviewed papers published since the mid of the last century, and the most cited papers of the last ten years. Results:: Studies indicate that thymoquinone possesses immunomodulatory activities, in addition to its chemopreventive role, as thymoquinone can target and modulate inflammatory molecules, like nuclear factor kappa B (NF-κβ), interleukins, tumor necrosis factor-α (TNF-α), and certain growth factors. As chronic inflammation plays an important role in cancer development, controlling inflammatory pathways is an important mechanism of an anticancer molecule, and modulation of inflammatory pathways might be one of the key mechanisms of thymoquinone’s anticancer activities. Conclusion: : This article reviewed the role of inflammation on cancer development, and the action of thymoquinone on inflammatory molecules, which have been proved in vitro and in vivo. Much attention is required for studying the role of thymoquinone in immunotherapeutics and developing this molecule as a future anticancer drug.

scholarly journals Inorganic polyphosphate potentiates lipopolysaccharide-induced macrophage inflammatory response

2020 ◽  
Vol 295 (12) ◽  
pp. 4014-4023
Author(s):  
Toru Ito ◽  
Suguru Yamamoto ◽  
Keiichi Yamaguchi ◽  
Mami Sato ◽  
Yoshikatsu Kaneko ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Cell Biology ◽  
Immune Cell ◽  
Critical Role ◽  
Binding Assays ◽  
Inorganic Polyphosphate ◽  
Cell Dysfunction ◽  
Factor Α

Inorganic polyphosphate (polyP) is a linear polymer of orthophosphate units that are linked by phosphoanhydride bonds and is involved in various pathophysiological processes. However, the role of polyP in immune cell dysfunction is not well-understood. In this study, using several biochemical and cell biology approaches, including cytokine assays, immunofluorescence microscopy, receptor-binding assays with quartz crystal microbalance, and dynamic light scanning, we investigated the effect of polyP on in vitro lipopolysaccharide (LPS)-induced macrophage inflammatory response. PolyP up-regulated LPS-induced production of the inflammatory cytokines, such as tumor necrosis factor α, interleukin-1β, and interleukin-6, in macrophages, and the effect was polyP dose– and chain length–dependent. However, orthophosphate did not exhibit this effect. PolyP enhanced the LPS-induced intracellular macrophage inflammatory signals. Affinity analysis revealed that polyP interacts with LPS, inducing formation of small micelles, and the polyP-LPS complex enhanced the binding affinity of LPS to Toll-like receptor 4 (TLR4) on macrophages. These results suggest that inorganic polyP plays a critical role in promoting inflammatory response by enhancing the interaction between LPS and TLR4 in macrophages.

scholarly journals Tumor Necrosis Factor-α Triggers Mucus Production in Airway Epithelium through an IκB Kinase β-dependent Mechanism

2005 ◽  
Vol 280 (43) ◽  
pp. 36510-36517 ◽  
Author(s):  
José M. Lora ◽  
Dong Mei Zhang ◽  
Sha Mei Liao ◽  
Timothy Burwell ◽  
Anne Marie King ◽  
...  
Keyword(s):  
Airway Epithelium ◽  
Transforming Growth Factor ◽  
Mucus Production ◽  
Transforming Growth Factor Α ◽  
Iκb Kinase ◽  
Tnf Α ◽  
Factor Α

Excessive mucus production by airway epithelium is a major characteristic of a number of respiratory diseases, including asthma, chronic bronchitis, and cystic fibrosis. However, the signal transduction pathways leading to mucus production are poorly understood. Here we examined the potential role of IκB kinase β (IKKβ) in mucus synthesis in vitro and in vivo. Tumor necrosis factor-α (TNF-α) or transforming growth factor-α stimulation of human epithelial cells resulted in mucus secretion as measured by MUC5AC mRNA and protein. TNF-α stimulation induced IKKβ-dependent p65 nuclear translocation, mucus synthesis, and production of cytokines from epithelial cells. TNF-α, but not transforming growth factor-α, induced mucus production dependent on IKKβ-mediated NF-κB activation. In vivo, TNF-α induced NF-κB as determined by whole mouse body bioluminescence. This activation was localized to the epithelium as revealed by LacZ staining in NF-κB-LacZ transgenic mice. TNF-α-induced mucus production in vivo could also be inhibited by administration into the epithelium of an IKKβ dominant negative adenovirus. Taken together, our results demonstrated the important role of IKKβ in TNF-α-mediated mucus production in airway epithelium in vitro and in vivo.

scholarly journals Ubiquitin fold modifier 1 activates NF-κB pathway by down-regulating LZAP expression in the macrophage of diabetic mouse model

2020 ◽  
Vol 40 (1) ◽  
Author(s):  
Xiaolei Hu ◽  
Hengyan Zhang ◽  
Yuan Song ◽  
Langen Zhuang ◽  
Qingqing Yang ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Diabetic Mouse ◽  
Peritoneal Macrophages ◽  
Raw264.7 Cells ◽  
Luciferase Reporter ◽  
Tnf Α ◽  
Cytokine Levels ◽  
Factor Α ◽  
Necrosis Factor

Abstract Inflammatory response is closely related with the development of many serious health problems worldwide including diabetes mellitus (DM). Ubiquitin-fold modifer 1 (Ufm1) is a newly discovered ubiquitin-like protein, while its function remains poorly investigated, especially in inflammatory response and DM. In the present study, we analyzed the role of Ufm1 on inflammatory response in DM, and found that the proinflammatory cytokine levels (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-1β) and Ufm1 expression were highly increased both in the peritoneal macrophages of db/db mice and Raw264.7 cells induced by lipopolysaccharide (LPS). Western blot and luciferase reporter assay showed that NF-κB pathway was obviously activated in macrophages and the expression of LZAP, an inhibitor of NF-κB pathway, was down-regulated. With the LZAP knockdown plasmid and activation plasmid, we demonstrated that NF-κB/p65 activation was inhibited by LZAP in macrophages. The interaction of Ufm1 and LZAP was further proved with co-immunoprecipitation assay in HEK293 and Raw264.7 cells. The LZAP expression was also related with the presence of Ufm1 demonstrated by Ufm1 knockdown plasmid and activation plasmid. Besides that, we finally proved that the expression and activation of Ufm1 induced by LPS were regulated by JNK/ATF2 and JNK/c-Jun pathway with the use of SP600125. In conclusion, the present study demonstrated that Ufm 1 could activate NF-κB pathway by down-regulating LZAP in macrophage of diabetes, and its expression and activation were regulated by JNK/ATF2 and c-Jun pathway.

scholarly journals CD109 regulates the inflammatory response and is required for the pathogenesis of rheumatoid arthritis

2019 ◽  
Vol 78 (12) ◽  
pp. 1632-1641 ◽  
Author(s):  
Guanhua Song ◽  
Tingting Feng ◽  
Ru Zhao ◽  
Qiqi Lu ◽  
Yutao Diao ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Response ◽  
Osteoclast Differentiation ◽  
Small Interfering Rnas ◽  
Inflammatory Stimuli ◽  
Synovial Tissues ◽  
Factor Α ◽  
Fibroblast Like Synoviocytes

ObjectiveThe aim of this study was to investigate the role of CD109 in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLSs) and to evaluate its potential as a therapeutic target.MethodsCD109 expression was examined in synovial tissues and FLSs from RA patients and collagen-induced arthritis (CIA) model mice. CD109-deficient mice were developed to evaluate the severity of CIA. Small interfering RNAs and a neutralising antibody against CD109 (anti-CD109) were designed for functional or treatment studies in RA FLSs and CIA.ResultsCD109 was found to be abundantly expressed in the synovial tissues from RA patients and CIA mice. CD109 expression in RA FLSs was upregulated by inflammatory stimuli, such as interleukin-1β and tumour necrosis factor-α. Silencing of CD109 or anti-CD109 treatment reduced proinflammatory factor production, cell migration, invasion, chemoattractive potential and osteoclast differentiation, thereby reducing the deleterious inflammatory response of RA FLSs in vitro. Mice lacking CD109 were protected against arthritis in the CIA model. Anti-CD109 treatment prevented the onset and ameliorated the severity of CIA lesions.ConclusionOur study uncovers an antiarthritic role for CD109 and suggests that CD109 inhibition might serve as a promising novel therapeutic strategy for RA.

scholarly journals NOD1/RIP2 signalling enhances the microglia-driven inflammatory response and undergoes crosstalk with inflammatory cytokines to exacerbate brain damage following intracerebral haemorrhage in mice

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Miao Wang ◽  
Xinchun Ye ◽  
Jinxia Hu ◽  
Qiuchen Zhao ◽  
Bingchen Lv ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Brain Damage ◽  
Microglial Activation ◽  
Inflammatory Factors ◽  
Primary Microglia ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

Abstract Background Secondary brain damage caused by the innate immune response and subsequent proinflammatory factor production is a major factor contributing to the high mortality of intracerebral haemorrhage (ICH). Nucleotide-binding oligomerization domain 1 (NOD1)/receptor-interacting protein 2 (RIP2) signalling has been reported to participate in the innate immune response and inflammatory response. Therefore, we investigated the role of NOD1/RIP2 signalling in mice with collagenase-induced ICH and in cultured primary microglia challenged with hemin. Methods Adult male C57BL/6 mice were subjected to collagenase for induction of ICH model in vivo. Cultured primary microglia and BV2 microglial cells (microglial cell line) challenged with hemin aimed to simulate the ICH model in vitro. We first defined the expression of NOD1 and RIP2 in vivo and in vitro using an ICH model by western blotting. The effect of NOD1/RIP2 signalling on ICH-induced brain injury volume, neurological deficits, brain oedema, and microglial activation were assessed following intraventricular injection of either ML130 (a NOD1 inhibitor) or GSK583 (a RIP2 inhibitor). In addition, levels of JNK/P38 MAPK, IκBα, and inflammatory factors, including tumour necrosis factor-α (TNF-α), interleukin (IL)-1β, and inducible nitric oxide synthase (iNOS) expression, were analysed in ICH-challenged brain and hemin-exposed cultured primary microglia by western blotting. Finally, we investigated whether the inflammatory factors could undergo crosstalk with NOD1 and RIP2. Results The levels of NOD1 and its adaptor RIP2 were significantly elevated in the brains of mice in response to ICH and in cultured primary microglia, BV2 cells challenged with hemin. Administration of either a NOD1 or RIP2 inhibitor in mice with ICH prevented microglial activation and neuroinflammation, followed by alleviation of ICH-induced brain damage. Interestingly, the inflammatory factors interleukin (IL)-1β and tumour necrosis factor-α (TNF-α), which were enhanced by NOD1/RIP2 signalling, were found to contribute to the NOD1 and RIP2 upregulation in our study. Conclusion NOD1/RIP2 signalling played an important role in the regulation of the inflammatory response during ICH. In addition, a vicious feedback cycle was observed between NOD1/RIP2 and IL-1β/TNF-α, which could to some extent result in sustained brain damage during ICH. Hence, our study highlights NOD1/RIP2 signalling as a potential therapeutic target to protect the brain against secondary brain damage during ICH.

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