The Role of Interleukin-1 in the Pathogenesis of Cancer and its Potential as a Therapeutic Target in Clinical Practice.
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ABSTRACT:
SUBMITTER: Litmanovich A
PROVIDER: S-EPMC7359982 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundExtended criteria donor lungs deemed unsuitable for immediate transplantation can be reconditioned using ex vivo lung perfusion (EVLP). Objective identification of which donor lungs can be successfully reconditioned and will function well post-operatively has not been established. This study assessed the predictive value of markers of inflammation and tissue injury in donor lungs undergoing EVLP as part of the DEVELOP-UK study.MethodsLongitudinal samples of perfusate, bronchoalveolar lavage, and tissue from 42 human donor lungs undergoing clinical EVLP assessments were analyzed for markers of inflammation and tissue injury. Levels were compared according to EVLP success and post-transplant outcomes. Neutrophil adhesion to human pulmonary microvascular endothelial cells (HPMECs) conditioned with perfusates from EVLP assessments was investigated on a microfluidic platform.ResultsThe most effective markers to differentiate between in-hospital survival and non-survival post-transplant were perfusate interleukin (IL)-1? (area under the curve = 1.00, p = 0.002) and tumor necrosis factor-? (area under the curve = 0.95, p = 0.006) after 30 minutes of EVLP. IL-1? levels in perfusate correlated with upregulation of intracellular adhesion molecule-1 in donor lung vasculature (R2 = 0.68, p < 0.001) and to a lesser degree upregulation of intracellular adhesion molecule-1 (R2 = 0.30, p = 0.001) and E-selectin (R2 = 0.29, p = 0.001) in conditioned HPMECs and neutrophil adhesion to conditioned HPMECs (R2 = 0.33, p < 0.001). Neutralization of IL-1? in perfusate effectively inhibited neutrophil adhesion to conditioned HPMECs (91% reduction, p = 0.002).ConclusionsDonor lungs develop a detectable and discriminatory pro-inflammatory signature in perfusate during EVLP. Blocking the IL-1? pathway during EVLP may reduce endothelial activation and subsequent neutrophil adhesion on reperfusion; this requires further investigation in vivo.
| S-EPMC5578478 | biostudies-literature
Project description:Acute pancreatitis (AP) is one of the most common diseases in gastroenterology. However, neither the etiology nor the pathophysiology of the disease is fully understood and no specific or effective treatment has been developed. Heparanase is an endoglycosidase that cleaves heparan sulfate (HS) side chains of HS sulfate proteoglycans into shorter oligosaccharides, activity that is highly implicated in cellular invasion associated with cancer metastasis and inflammation. Given that AP involves a strong inflammatory aspect, we examined whether heparanase plays a role in AP. Here, we provide evidence that pancreatic heparanase expression and activity are significantly increased following cerulein treatment. Moreover, pancreas edema and inflammation, as well as the induction of cytokines and signaling molecules following cerulein treatment were attenuated markedly by heparanase inhibitors, implying that heparanase plays a significant role in AP. Notably, all the above features appear even more pronounced in transgenic mice over expressing heparanase, suggesting that these mice can be utilized as a sensitive model system to reveal the molecular mechanism by which heparanase functions in AP. Heparanase, therefore, emerges as a potential new target in AP, and heparanase inhibitors, now in phase I/II clinical trials in cancer patients, are hoped to prove beneficial also in AP.
| S-EPMC5429646 | biostudies-literature
Project description:INTRODUCTION:Interleukin-6 (IL-6) is an important growth factor for estrogen receptor-? (ER?)-positive breast cancer, and elevated serum IL-6 is associated with poor prognosis. METHODS:The role of the phosphorylated signal transducer and activator of transcription 3 pathway was investigated in ER?-positive breast cancer. A panel of cell lines was treated with exogenous IL-6. An IL-6 specific gene signature was generated by profiling ten ER?-positive breast cancer cell lines alone or following treatment with 10 ng/mL recombinant IL-6 or human marrow stromal cell-conditioned media, with or without siltuximab (a neutralizing anti-IL-6 antibody) and grown in three-dimensional tumor microenvironment-aligned cultures for 4 days, 5 days, or 6 days. The established IL-6 signature was validated against 36 human ER?-positive breast tumor samples with matched serum. A comparative MCF-7 xenograft murine model was utilized to determine the role of IL-6 in estrogen-supplemented ER?-positive breast cancer to assess the efficacy of anti-IL-6 therapy in vivo. RESULTS:In eight of nine ER?-positive breast cancer cell lines, recombinant IL-6 increased phosphorylation of tyrosine 705 of STAT3. Differential gene expression analysis identified 17 genes that could be used to determine IL-6 pathway activation by combining their expression intensity into a pathway activation score. The gene signature included a variety of genes involved in immune cell function and migration, cell growth and apoptosis, and the tumor microenvironment. Validation of the IL-6 gene signature in 36 matched human serum and ER?-positive breast tumor samples showed that patients with a high IL-6 pathway activation score were also enriched for elevated serum IL-6 (?10 pg/mL). When human IL-6 was provided in vivo, MCF-7 cells engrafted without the need for estrogen supplementation, and addition of estrogen to IL-6 did not further enhance engraftment. Subsequently, we prophylactically treated mice at MCF-7 engraftment with siltuximab, fulvestrant, or combination therapy. Siltuximab alone was able to blunt MCF-7 engraftment. Similarly, siltuximab alone induced regressions in 90% (9/10) of tumors, which were established in the presence which were established in the presence of hMSC expressing human IL-6 and estrogen. CONCLUSION:Given the established role for IL-6 in ER?-positive breast cancer, these data demonstrate the potential for anti-IL-6 therapeutics in breast cancer.
| S-EPMC4745841 | biostudies-literature
Project description:Acute kidney injury (AKI) causes over 1 million deaths worldwide every year. AKI is now recognized as a major risk factor in the development and progression of chronic kidney disease (CKD). Diabetes is the main cause of CKD as well. Renal fibrosis and inflammation are hallmarks in kidney diseases. Various cytokines contribute to the progression of renal diseases; thus, many drugs that specifically block cytokine function are designed for disease amelioration. Numerous studies showed IL-20 functions as a pro-inflammatory mediator to regulate cytokine expression in several inflammation-mediated diseases. In this review, we will outline the effects of pro-inflammatory cytokines in the pathogenesis of AKI and CKD. We also discuss the role of IL-20 in kidney diseases and provide a potential therapeutic approach of IL-20 blockade for treating renal diseases.
| S-EPMC7037658 | biostudies-literature
Project description:Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 novel coronavirus, has spread worldwide causing high fatality rates. Neither a vaccine nor specific therapeutic approaches are available, hindering the fight against this disease and making better understanding of its pathogenesis essential. Despite similarities between SARS-CoV-2 and SARS-CoV, the former has unique characteristics which represent a great challenge to physicians. The mechanism of COVID-19 infection and pathogenesis is still poorly understood. In the present review, we highlight possible pathways involved in the pathogenesis of COVID-19 and potential therapeutic targets, focusing on the role of the renin-angiotensin-aldosterone system.
| S-EPMC7357286 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2016-02-04 | GSE54331 | GEO
Project description:A unique feature of the cytokine storm in coronavirus disease 2019 (COVID-19) is the dramatic elevation of interleukin 10 (IL-10). This was thought to be a negative feedback mechanism to suppress inflammation. However, several lines of clinical evidence suggest that dramatic early proinflammatory IL-10 elevation may play a pathological role in COVID-19 severity.
| S-EPMC7605819 | biostudies-literature
Project description:There is a critical need for alternative, potent agents that can reduce low-density lipoprotein cholesterol (LDL-C) levels in patients with heterozygous familial hyperlipidemia and statin intolerance and those not reaching lipid-lowering treatment goals who are at high risk for cardiovascular (CV) events. The first proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor was approved in July 2015 by the US Food and Drug Administration as an adjunct to diet and maximally tolerated statin therapy for treatment of adults with heterozygous familial hyperlipidemia or clinical atherosclerotic CV disease, who require additional lowering of LDL-C levels. In clinical trials, PCSK9 inhibitors have been shown to reduce LDL-C levels by as much as 60% to 70% when administered as monotherapy or as an add-on treatment to statins and other lipid-lowering therapies. In studies of PCSK9 genetic mutations, loss of function in the PCSK9 allele was associated with a relative decrease of 88% in the risk for atherosclerotic CV events during 15 years of patient follow-up. The use of PCSK9 inhibitors may eventually support the LDL-C hypothesis that the lower the LDL-C level, the lower the CV risk. Although some recent clinical practice guidelines have deemphasized the importance of numeric LDL-C targets, many clinicians are reluctant to discard them, and this position is supported by recent clinical evidence. We eagerly await the results of the ODYSSEY, FOURIER, and SPIRE clinical outcome trials, which we anticipate will provide further validation that "lower is better" with respect to reducing LDL-C levels and improving clinical outcomes.
| S-EPMC4719137 | biostudies-other
Project description:The present study aimed to reveal the metabolic alterations of the extracellular matrix (ECM) in uterosacral ligament (USL) with pelvic organ prolapse (POP) and to explore the role of transforming growth factor??1 (TGF??1) in pathogenesis of POP. For this purpse, 60 participants who underwent hysterectomy for benign indications were enrolled, 30 of which had symptomatic POP (grade II, III or IV) and composed the POP group, and the other 30 had asymptomatic POP (grade I or less) and served as the controls. Collagen fibers, elastin,matrix metalloproteinase (MMP)?2/9, tissue inhibitor of matrix metalloproteinases (TIMP)?2 and TGF??1 were examined by Masson's trichrome staining, immunohistochemistry and RT-qPCR using USL biopsies. In vitro, human USL fibroblasts (hUSLFs) were primary cultured, pre-treated with recombinant TGF??1 (0, 5, or 10 ng/ml) and then subjected to cyclic mechanical stretching (CMS; 0 or 5,333 µ? strain). Changes in the expression levels of collagen type I/III, elastin, TIMP?2, MMP?2/9 and Smad were detected. Our results revealed that at the tissue level, the expression of collagen fibers, elastin, TIMP?2 and TGF??1 was significantly reduced in the POP group, while the activities of MMP?2/9 were significantly upregulated, compared with the control group. Statistical analysis indicated that the mRNA expression of TGF??1 inversely correlated with the severity of POP partially. Our in vitro experimental data demonstrated that a CMS of 5333 µ? strain promoted the degradation of ECM proteins, inhibited the synthesis of TIMP?2, and upregulated the proteolytic activities of MMP?2/9. Pre-treatment with TGF??1 attenuated the loss of ECM by stimulating the synthesis of TIMP?2 and inhibiting the activities of MMP?2/9 through the TGF??1/Smad3 signaling pathway. On the whole, our data indicate that the reduced anabolism and increased catabolism of ECM proteins in USL are the pathological characteristics of POP. TGF??1 not only has a specific value in predicting the severity of POP, but should also be considered as a novel therapeutic target for POP.
| S-EPMC5504969 | biostudies-literature
Project description:Werner syndrome (WS) is a prototypical segmental progeroid syndrome characterized by multiple features consistent with accelerated aging. It is caused by null mutations of the WRN gene, which encodes a member of the RECQ family of DNA helicases. A unique feature of the WRN helicase is the presence of an exonuclease domain in its N-terminal region. Biochemical and cell biological studies during the past decade have demonstrated involvements of the WRN protein in multiple DNA transactions, including DNA repair, recombination, replication and transcription. A role of the WRN protein in telomere maintenance could explain many of the WS phenotypes. Recent discoveries of new progeroid loci found in atypical Werner cases continue to support the concept of genomic instability as a major mechanism of biological aging. Based on these biological insights, efforts are underway to develop therapeutic interventions for WS and related progeroid syndromes.
| S-EPMC5025328 | biostudies-literature