scholarly journals Acacia ferruginea Inhibits Tumor Progression by Regulating Inflammatory Mediators-(TNF-α, iNOS, COX-2, IL-1β, IL-6, IFN-γ, IL-2, GM-CSF) and Pro-Angiogenic Growth Factor-VEGF

2013 ◽  
Vol 14 (6) ◽  
pp. 3909-3919 ◽  
Author(s):  
Kunnathur Murugesan Sakthivel ◽  
Chandrasekaran Guruvayoorappan
Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2490-2490
Author(s):  
Carolina Lanaro ◽  
Carla Fernanda Franco-Penteado ◽  
Dulcinéia M Albuquerque ◽  
Sara T.O. Saad ◽  
Nicola Conran ◽  
...  

Abstract Leukocytosis is frequently observed in sickle cell disease (SCD) in the absence of bacterial infection. An elevated baseline leukocyte count is associated with an increased risk of early death and leukocytes play a significant role in the initiation of vaso-occlusive events. Inflammation, cell adhesion to vascular endothelium, and subsequent endothelial injury appear to contribute to sickle cell anemia (SCA) vaso-occlusion. Furthermore, blood levels of inflammatory and anti-inflammatory cytokines are reported to be elevated (TNF-α, IL-6, IL-10, GM-CSF), both in steady state and during crisis, but reports have been conflicting and a conclusive role for these molecules in the disease remains to be established. Furthermore, the effect of hydroxyurea therapy (HU) on the release of inflammatory mediators is not understood. The aim of this study was to determine plasma levels and leukocyte gene expressions of inflammatory mediators in healthy controls (n=30), steady-state SCA patients (n=45) and SCA patients on HU therapy (n=24). qRT-PCR analysis was use to examine gene expression and ELISA protein production. TNF-α, IL-8 and PGE2 plasma levels were significantly higher in the plasma of steady-state SCA individuals, when compared to control individuals (2.95 ± 0.4 pg/ml; 16.5 ± 2.5 pg/ml; 5.7 ± 0.6 pg/ml; 128.3 ± 12.2 pg/ml vs 1.43 ± 0.2 pg/ml, 88.5 ± 5.9 pg/ml, P=0.006; P<0.0001; P=0.012, respectively). HU therapy significantly reversed augmented TNF-α (1.6 ± 0.2 pg/ml, P=0.006) and, interestingly, increased plasma anti-inflammatory IL-10 (P<0.05). IL-10, IFN-γ, COX-2 and iNOS gene expressions were unaltered in SCA mononuclear cells (MC), however gene expressions of TNF-α, IL-8 and the protective enzyme, heme oxygenase-1 (HO-1), were significantly higher compared to healthy controls (0.46 ± 0.01; 0.08 ± 0.02; 0.21 ± 0.05 vs 0.18 ± 0.04; 0.02 ± 0.005; 0.035 ± 0.008; respectively, P<0.02). HU therapy was not associated with significantly altered SCA MC inflammatory gene expression, although COX-2 mRNA expression was decreased (0.11 ± 0.05; 0.37 ± 0.12, SCAHU and SCA, respectively; P<0.05). In SCA neutrophils, gene expressions of IL-8, IFN-γ, iNOS and HO-1 were significantly higher compared to those of control subjects (0.32 ± 0.07; 0.69 ± 0.19; 0.19 ± 0.06; 0.33 ± 0.09, P=0.02, P=0.025, P<0.05; P=0.027, respectively). Patients on HU therapy demonstrated lower iNOS and higher IL-10 neutrophil gene expressions compared to SCA not on HU therapy (0.038 ± 0.03; 0.72 ± 0.13, P<0.05; P<0.05, respectively). Taken together, data suggest that alterations in the gene expressions and productions of a number of pro-and anti-inflammatory mediators are present in SCA and knowledge of these pathways may be important for identifying novel drug targets for the disease.


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5246-5246 ◽  
Author(s):  
Tomas Kupsa ◽  
Jan Vanek ◽  
Pavel Zak ◽  
Ladislav Jebavy ◽  
Jan M. Horacek

Abstract Background: Cytokines, cytokine receptors and adhesion molecules have been studied as markers of immune system activation in various diseases including AML/MDS. These factors form a dynamic network which affects AML cell susceptibility to chemotherapy. To provide more evidence of these interactions, we analyzed the serum levels of a broad panel of cytokines, cytokine receptors, matrix metalloproteinase-9 and soluble adhesion molecules. Aims: The aim of our study was to evaluate hypothesis that baseline serum levels of these factors are associated with relapse and overall survival (OS). Methods: A total of 65 AML patients (27 males, 38 females, mean age 53.7 ± 12.8, median 57.1 years) newly diagnosed in the period 2011 - 2014 were analyzed. All patients were Caucasian. Of these, 14 had better risk, 10 intermediate-1 risk, 13 intermediate-2 risk and 28 high risk AML according to ELN risk stratification (Döhner et al., Blood 2010). The NPM-1 was mutated in 16 cases, the FLT3-ITD was present in 15 cases. The secondary disease was present in 26 cases, 3 patients were BCR/ABL positive. Five patients with APL were treated with the PETHEMA regimen combining Idarubicin and All-trans retinoic acid (ATRA). All other patients were induced with "3+7" induction chemotherapy consisting of Cytarabin 100mg/m2 per day for 7 consecutive days and Daunorubicin 90mg/m2 for the first 3 days of therapy in younger patients. In patients aged ≥ 65 years, Daunorubicin 45-60mg/m2 was administered, depending on patient WHO performance status. We evaluated baseline circulating levels of the following factors: interleukins (IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-15), epidermal growth factor (EGF), granulocyte-macrophage colony stimulating factor (GM-CSF), interferon-gamma (IFN-γ), monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), matrix-metalloproteinase-9 (MMP-9), tumor necrosis factor-alpha (TNF-α), vascular endothelial growth factor (VEGF), soluble IL-2 receptor-α (sIL-2Rα) and soluble receptors for IL-6 (sIL-6R) and TNF-α type I and II (TNFR-1,2), E-selectin (E-SEL), P-selectin (P-SEL), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). All biomarkers were measured by biochip array technology on Evidence Investigator analyzer (Randox). Statistical analysis was performed in R 3.1.2. Probability values (P) < 0.05 were considered statistically significant. Results: All evaluated analytes were independent of age, disease origin and ELN risk stratification. Relapse occurred in 34 cases with median of 516 days. Median follow-up was 627 days. Primary AML, normal karyotype and achieving of complete remission (CR) after induction therapy were associated with better relapse free survival (RFS), whereas higher TNFR-1, VEGF, IL-3, TNFR-2, NPM-1 and BCR/ABL were associated with inferior RFS. OS correlated with levels of IFN-γ, GM-CSF and TNFR-1. In multivariate analysis, primary AML, higher IL-10 and IL-15 were associated longer OS. Higher age, higher ELN risk and higher levels of TNFR-1, IL-3, IL-6, IL-8 and TNFR-2 were associated with inferior OS. Conclusions: Cytokines are an important part of cancer environment. In AML, some cytokines or their receptors may be informative for individual prognosis. The literature suggests association of IL-6 and IL-10 levels and OS (Correa et al., Cytokine 2013). Our data are in agreement with this finding, but revealed more cytokines and their receptors, especially TNFR-1, which were independently associated with relapse and OS. To confirm these findings, analysis in a larger cohort with longer follow-up should be performed. Acknowledgment: The work was supported by a specific research project "Analysis of defined prognostic factors in acute myeloid leukemia" (FMHS Hradec Kralove), by a long-term organization development plan 1011 (FMHS Hradec Kralove) and by MH CZ - DRO (UHHK, 00179906). Disclosures No relevant conflicts of interest to declare.


2018 ◽  
Vol 32 ◽  
pp. 205873841878799 ◽  
Author(s):  
Alexander Autenshlyus ◽  
Sergey Arkhipov ◽  
Elena Mikhailova ◽  
Valentina Arkhipova ◽  
Nikolay Varaksin

Currently, the role of cytokines in the tumor progression, including breast cancer, is universally recognized. At the same time, there are still many questions concerning the role of individual cytokines and receptors for cytokines in various morphogenetic processes underlying the tumor progression. The objective of this work was to study cytokine production and vascular endothelial growth factor (VEGF)-R2 and VEGF-R1 expression by mammary adenocarcinoma (MAC) and the correlations with histopathological parameters of malignant tumors. The object of the study was cultured tumor biopsy samples from 47 women aged 43–75 years with invasive ductal carcinoma, which was classified as grade II–III adenocarcinoma. It was shown that the cytokine profiles of the supernatants of MAC samples from patients differ greatly. A correlation between the levels of VEGF-R2 and tumor necrosis factor (TNF)-R1 expression was observed. Correlations were also revealed during analysis of the relations of histopathological MAC indicators with KVEGF-R2/VEGF-A and KTNF-R1/TNF-α coefficients, which are equal, respectively, to the ratio of expression values of receptors VEGF-R2 and TNF-R1 to the concentrations of the relevant cytokines (VEGF-A and TNF-α) in the culture supernatants of the same MAC samples. A direct correlation was identified between KVEGF-R/VEGF-A and some histopathological MAC characteristics: proportion of cells undergoing mitosis or pathological mitosis in MAC and poorly differentiated cells. KVEGF-R2/VEGF-A directly correlated with the concentration in supernatant interleukin (IL)-18 and interferon (IFN)-γ. KTNF-R1/TNF-α was inversely correlated with the concentration in supernatant of IL-1Ra, IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF). The data obtained show that the high-level production of IL-18 and IL-1β by MAC, overexpression of VEGF-R2 in tumor (at relatively low VEGF-A production), and the high level of IFN-γ production are attributed factors contributing to the formation of a population of low-grade cells in the tumor. The factors regulating the population of moderately differentiated cells in the tumor are referred to as IL-1Ra, IL-8, and GM-CSF.


Critical Care ◽  
2021 ◽  
Vol 25 (1) ◽  
Author(s):  
Nuttha Lumlertgul ◽  
Anna Hall ◽  
Luigi Camporota ◽  
Siobhan Crichton ◽  
Marlies Ostermann

Abstract Background The EMiC2 membrane is a medium cut-off haemofilter (45 kiloDalton). Little is known regarding its efficacy in eliminating medium-sized cytokines in sepsis. This study aimed to explore the effects of continuous veno-venous haemodialysis (CVVHD) using the EMiC2 filter on cytokine clearance. Methods This was a prospective observational study conducted in critically ill patients with sepsis and acute kidney injury requiring kidney replacement therapy. We measured concentrations of 12 cytokines [Interleukin (IL) IL-1β, IL-1α, IL-2, IL-4, IL-6, IL-8, IL-10, interferon (IFN)-γ, tumour necrosis factor (TNF)-α, vascular endothelial growth factor, monocyte chemoattractant protein (MCP)-1, epidermal growth factor (EGF)] in plasma at baseline (T0) and pre- and post-dialyzer at 1, 6, 24, and 48 h after CVVHD initiation and in the effluent fluid at corresponding time points. Outcomes were the effluent and adsorptive clearance rates, mass balances, and changes in serial serum concentrations. Results Twelve patients were included in the final analysis. All cytokines except EGF concentrations declined over 48 h (p < 0.001). The effluent clearance rates were variable and ranged from negligible values for IL-2, IFN-γ, IL-1α, IL-1β, and EGF, to 19.0 ml/min for TNF-α. Negative or minimal adsorption was observed. The effluent and adsorptive clearance rates remained steady over time. The percentage of cytokine removal was low for most cytokines throughout the 48-h period. Conclusion EMiC2-CVVHD achieved modest removal of most cytokines and demonstrated small to no adsorptive capacity despite a decline in plasma cytokine concentrations. This suggests that changes in plasma cytokine concentrations may not be solely influenced by extracorporeal removal. Trial registration: NCT03231748, registered on 27th July 2017.


2001 ◽  
Vol 69 (1) ◽  
pp. 129-136 ◽  
Author(s):  
Julie Riopel ◽  
MiFong Tam ◽  
Karkada Mohan ◽  
Michael W. Marino ◽  
Mary M. Stevenson

ABSTRACT The contribution of granulocyte-macrophage colony-stimulating factor (GM-CSF), a hematopoietic and immunoregulatory cytokine, to resistance to blood-stage malaria was investigated by infecting GM-CSF-deficient (knockout [KO]) mice with Plasmodium chabaudi AS. KO mice were more susceptible to infection than wild-type (WT) mice, as evidenced by higher peak parasitemia, recurrent recrudescent parasitemia, and high mortality. P. chabaudiAS-infected KO mice had impaired splenomegaly and lower leukocytosis but equivalent levels of anemia compared to infected WT mice. Both bone marrow and splenic erythropoiesis were normal in infected KO mice. However, granulocyte-macrophage colony formation was significantly decreased in these tissues of uninfected and infected KO mice, and the numbers of macrophages in the spleen and peritoneal cavity were significantly lower than in infected WT mice. Serum levels of gamma interferon (IFN-γ) were found to be significantly higher in uninfected KO mice, and the level of this cytokine was not increased during infection. In contrast, IFN-γ levels were significantly above normal levels in infected WT mice. During infection, tumor necrosis factor alpha (TNF-α) levels were significantly increased in KO mice and were significantly higher than TNF-α levels in infected WT mice. Our results indicate that GM-CSF contributes to resistance to P. chabaudi AS infection and that it is involved in the development of splenomegaly, leukocytosis, and granulocyte-macrophage hematopoiesis. GM-CSF may also regulate IFN-γ and TNF-α production and activity in response to infection. The abnormal responses seen in infected KO mice may be due to the lack of GM-CSF during development, to the lack of GM-CSF in the infected mature mice, or to both.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jin-Ho Joo ◽  
Hyejee Kim ◽  
Jae-Ho Shin ◽  
Sang Woong Moon

Abstract Background To identify disease-specific cytokine and growth factor profile differences in the aqueous humor between wet age-related macular degeneration (AMD) patients and age-matched controls and to correlate their levels with the optical coherence tomography (OCT) findings. Methods Aqueous humors were obtained from 13 wet AMD eyes and 10 control eyes. Twenty cytokines and growth factors were measured using a RayBio antibody microarray technology in wet AMD and control eyes. Results The samples obtained from wet AMD patients exhibited a significantly increased expression of MCP-1, MIP-1α, MIP-1β, and vascular endothelial growth factor (VEGF). Subretinal fluid (SRF) patients showed significantly lower levels of proinflammatory cytokines, such as IL-1α and GM-CSF, than those without SRF. Pigment epithelial detachments (PED) patients showed lower levels of inflammatory cytokines, such as GM-CSF, IFN-γ, and TNF-α, than those without PED. Subretinal tissue (SRT) patients showed a higher level of IFN-γ than those without SRT. Compared with the controls, type 1 macular neovascularization (MNV) patients showed increased levels of MCP-1, MIP-1α, and MIP-1β, but not VEGF (p = 0.083). However, type 2 MNV patients showed increased levels of MCP-1 and VEGF (p = 0.040 and p = 0.040). Conclusion Inflammatory cytokines varied according to the type of AMD- and OCT-based parameters. Our observation of low levels of VEGF in patients with type 1 MNV implies that the inhibition of VEGF alone appears to be insufficient treatment for these patients and that cytokines such as MCP-1, MIP-1α, and MIP-1β should be modulated. And the presence of SRF in MNV may be associated with a positive prognosis because we found relatively low levels of proinflammatory cytokines.


2004 ◽  
Vol 287 (3) ◽  
pp. G592-G598 ◽  
Author(s):  
Caroline Francoeur ◽  
Fabrice Escaffit ◽  
Pierre H. Vachon ◽  
Jean-François Beaulieu

Laminins are basement membrane molecules that mediate cell functions such as adhesion, proliferation, migration, and differentiation. In the normal small intestine, laminin-5 and -10 are mainly expressed at the base of villus cells. However, in Crohn's disease (CD), a major redistribution of these laminins to the crypt region of the inflamed ileal mucosa has been observed, suggesting a possible relationship between laminin expression and cytokine and/or growth factor production, which is also altered in CD. The aim of this study was to test the hypothesis that proinflammatory cytokines can modulate laminin expression by intestinal epithelial cells. The effect of TNF-α, IFN-γ, IL-1β, IL-6, and transforming growth factor (TGF)-β was analyzed on the expression of laminins in the normal human intestinal epithelial crypt (HIEC) cell line. When treated with a single cytokine, HIEC cells secreted small amounts of laminin-5 and -10. Only TNF-α and TGF-β induced a slight increase in the secretion of these laminins. However, in combination, TNF-α and IFN-γ synergistically stimulated the secretion of both laminin-5 and -10 in HIEC cells. Transcript analyses suggested that the upregulation of the two laminins might depend on distinct mechanisms. Interestingly, the TNF-α and IFN-γ combination was also found to significantly promote apoptosis. However, the effect of cytokines on the secretion of laminins was maintained even after completely blocking apoptosis by inhibiting caspase activities. These results demonstrate that laminin production is specifically modulated by the proinflammatory cytokines TNF-α and IFN-γ in intestinal epithelial cells under an apoptosis-independent mechanism.


2019 ◽  
Vol 8 (9) ◽  
pp. 1343 ◽  
Author(s):  
Timo A. Nees ◽  
Nils Rosshirt ◽  
Jiji A. Zhang ◽  
Tobias Reiner ◽  
Reza Sorbi ◽  
...  

The aim of this study was to identify inflammatory mediators of potential clinical relevance in synovial fluid (SF) samples of patients with knee osteoarthritis (OA). Therefore, radiographic OA severity, knee pain and function of 34 OA patients undergoing unicompartmental (UC) and bicompartmental (BC) knee arthroplasty were assessed prior to surgery and SF samples were analyzed for a broad variety of inflammatory mediators, including interleukins (ILs), interferons (IFNs), C-X-C motif ligand chemokines (CXCLs), and growth factors (nerve growth factor; NGF, vascular endothelial growth factor; VEGF, and stem cell growth factor β; SCGF-β) using multiplex assay. Significant differences were observed between the SF levels of different inflammatory markers. When compared to UC OA, significantly higher concentrations of IL-7, IL-8, IL-10, IL-12, IL-13, IFN-γ, VEGF and CXCL1 were detected in BC OA. Correlation analyses revealed significant associations between OA severity and IL-6, IL-8, IFN-γ, SCGF-β, VEGF, CXCL1. Interestingly, increases in both anti- (IL-10, IL-13) and pro-inflammatory (IL-7, IL-12, IFN-γ) cytokines, as well as growth factors (SCGF-β, VEGF), correlated significantly with the level of knee pain. Poorer knee function was associated with higher IL-6, IL-10, IL-12, IL-13, IL-18, βNGF, SCGF-β, VEGF and CXCL9 levels. In conclusion, this study provides an extensive profile of synovial inflammatory mediators in knee OA and identifies cytokines of potential clinical relevance. In fact, five of the mediators examined (IL-10, IL-12, IL-13, SCGF-β, VEGF) significantly correlate with both knee pain and function.


2006 ◽  
Vol 100 (4) ◽  
pp. 1124-1133 ◽  
Author(s):  
Frank Zaldivar ◽  
Jessica Wang-Rodriguez ◽  
Dan Nemet ◽  
Christina Schwindt ◽  
Pietro Galassetti ◽  
...  

Leukocytosis following exercise is a well-described phenomenon of stress/inflammatory activation in healthy humans. We hypothesized that, despite this increase in circulating inflammatory cells, exercise would paradoxically induce expression of both pro- and anti-inflammatory cytokines and growth factors within these cells. To test this hypothesis, 11 healthy adult men, 18–30 yr old, performed a 30-min bout of heavy cycling exercise; blood sampling was at baseline, end-exercise, and 60 min into recovery. The percentage of leukocytes positive for intracellular cytokines and growth factors and mean fluorescence intensity was obtained by flow cytometry. Proinflammatory cytokines (IL-1α, IL-2, IFN-γ, and TNF-α), a pleiotropic cytokine (IL-6), and anti-inflammatory cytokines and growth factors [IL-4, IL-10, growth hormone (GH), and IGF-I] were examined. Median fluorescence intensity was not affected by exercise; however, we found a number of significant changes ( P < 0.05 by mixed linear model and modified t-test) in the numbers of circulating cells positive for particular mediators. The pattern of expression reflected both pro- and anti-inflammatory functions. In T-helper lymphocytes, TNF-α, but also IL-6, and IL-4 were significantly increased. In monocytes, both IFN-γ and IL-4 increased. B-lymphocytes positive for GH and IGF-I increased significantly. GH-positive granulocytes also significantly increased. Collectively, these observations indicate that exercise primes an array of pro- and anti-inflammatory and growth factor expression within circulating leukocytes, perhaps preparing the organism to effectively respond to a variety of stressors imposed by exercise.


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