IL-33/ST2 axis in innate and acquired immunity to tumors

Interleukin-33, a ligand for ST2/T1, has an important role in allergy, autoimmunity and inflammation. The role of IL-33/ST2 axis in cancer is not elucidated. Using metastatic breast cancer model we provide evidence that lack of ST2 signaling led to reduced tumor growth and metastasis and enhanced anti-tumor immunity

IL-33/ST2 Pathway and Galectin-3 as a New Analytes in Pathogenesis and Cardiometabolic Risk Evaluation in Psychosis

Schizophrenia and treatment of this disorder are often accompanied with metabolic syndrome and cardiovascular issues. Alterations in the serum level of innate immune mediators, such as interleukin-33 (IL-33) and its receptor IL-33R (ST2) and Galectin-3 (Gal-3) were observed in these conditions. Moreover, these parameters are potential prognostic and therapeutic markers. There is also accumulating evidence that these molecules play a role in neuroinflammation. Therefore, in this study we have investigated the serum level of Gal-3, IL-33 and soluble ST2 (sST2) in different stages of schizophrenia. Gal-3 levels were elevated in remission and lower in schizophrenia exacerbation in comparison with controls. Levels of IL-33 and sST2 are higher in schizophrenia exacerbation in comparison with controls and patients in remission. This initial analysis of new markers of neuroinflammation suggested their involvement in schizophrenia pathophysiology and/or cardiometabolic comorbidity

Juvenile type granulosa cell tumor

© 2018, University of Kragujevac, Faculty of Science. All rights reserved. Granulosa cell tumor is a type of neoplasm, which represents 2-5% of all ovarian cancers. About 5% of these tumors are juvenile- type and usually occur to girls before puberty and to women younger than thirty years of age. There are signs premature puberty or premature emergence of secondary sexual characteristics with irregular vaginal bleeding that occur to these kind of patients. To the rare cases, like this, the occurrence of granulosa cell tumors can cause the appearance of hyperandrogenism with high levels of plasma testosterone, leading to virilization which happened to this female patient. We will present the female patient who was 35 years old and which was originally hospitalized to the Clinic for Haematology Clinical Center Kragujevac, because of extreme fatigue accompanied by dizziness. During diagnostics the patient underwent to the complete gynecological examination. After gynecological examinations and necessary diagnostic procedures, it was decided continuing the treatment at the Clinic of Gynecology and Obstetrics Clinical Center Kragujevac, where she underwent a total abdominal hysterectomy with bilateral salpingo- oophorectomy for suspected uterine neoplasm. Histopathological analysis of the obtained material confi rmed the presence of follicular cysts of both ovaries and juvenile type granulosa cell tumor on the right ovary; the uterus was enlarged with multiple fi broid tumors. Granulosa cell tumor should be suspected in the cases of girls and young females if there is present an ovarian cyst paired with signs of preterm puberty or hyperestrogenism. In this case, the presence of granulosa cell tumor was masked by signs of hyperandrogenism, which is not so typical, as well as the presence of uterine fi broids who have actually been the main cause for surgical treatment

Potential dual immunomodulatory role of VEGF in ulcerative colitis and colorectal carcinoma

Objective. Progression from ulcerative colitis (UC) toward colorectal carcinoma (CRC) is multistep process that includes gene alterations of tumor suppressor genes, such as p53 and p16. The aim of this study was to investigate the expression patterns of p16, p53 and VEGF in affected tissue and serum levels of cytokines TNF-α, IFN-γ, IL-4, IL-6, IL-10 and IL-17 in patients with UC and CRC, respectively. Matherials and methods. Serum levels of cytokine in patients with UC (n=24) and CRC (n=75) and in a healthy group (n=37) were analyzed by ELISA. Endoscopic biopsies specimens of UC and CRC were studied by immunohistochemical staining for p16, p53 and VEGF. Results. Patients with UC with presence of extraintestinal manifestations, complications, and positive staining of p16, p53 and VEGF respectively had higher serum levels of pro-inflammatory cytokines. Higher percentage of CRC patients had positive staining of p16, p53 and VEGF. CRC patients with positive staining of VEGF had decreased systemic values of pro-inflammatory IFN-γ and increased values of immunosuppressive IL-10. Conclusions. Relatively low IL-10 in patients with severe UC is insufficient to compensate IL-6 secretion and subsequently enhanced type 1/17 immune response. In UC patients, p16 and p53 induce enhanced VEGF expression and subsequent production of pro-inflammatory TNF-α and IL-6. In CRC patients VEGF seems to have immunosuppressive role. It appears that tumor suppressor gene-VEGF axis have dual role on immune response in inflammation of UC and tumor growth and progression of CRC. © Ivyspring International Publisher

Suppression of natural killer-cell and dendritic-cell apoptotic tumoricidal activity in patients with head and neck cancer

Background Natural killer (NK) cells and dendritic cells (DCs) mediate tumor cell apoptosis using tumor necrosis factor superfamily ligands (TNFSFLs). This cytotoxicity is an important anticancer immune defense mechanism. Methods We examined TNFSFL expression and apoptotic tumoricidal activity (ATA) of purified NK cells and DCs, and peripheral blood mononuclear leukocytes (PBMLs) of healthy individuals and patients with head and neck cancer (HNC) before and after cancer ablation. Results PBMLs, NK cells and DCs, but not NK-cell/DC-depleted PBMLs, expressed multiple TNFSFLs and mediated ATA. Both TNFSFL expression and ATA were suppressed in tumor-bearing, and restored in tumor-ablated patients with (HNC) Soluble TNF superfamily receptors (solTNFSFRs) were increasingly bound by PBNLs of tumor-bearing HNC patients. Dissociation of solTNFSFR led to more pronounced increases in TNFSFL expression and ATA of PBMLs of patients with HNC than healthy individuals. Conclusion NK-cell and DC TNFSFL expression and ATA are suppressed in patients with HNC. This suppression is tumor-dependent and possibly mediated by solTNFSFRs. © 2012 Wiley Periodicals, Inc

O,O'-diethyl-(S,S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl) propanoate dihydrochloride enhances influx of effective NK and NKT cells in murine breast cancer

© 2020 Inst. Sci. inf., Univ. Defence in Belgrade. All rights reserved. Background/Aim. O,O'-diethyl-(S,S)-ethylenediamineN,N'-di-2-(3-cyclohexyl)propanoate dihydrochloride (DE-EDCP) has been found to possess promising cytotoxic activity against various tumor cell lines. Also, DE-EDCP reduces tumor progression by several mechanisms such as triggering tumor cell death and inhibition of cell proliferation. The aim of present study was to further evaluate antitumor activity of DE-EDCP by investigating effects on migratory potential of tumor cells and anti-tumor immune response. Methods. Migratory potential of DE-EDCP was evaluated by scratch wound assay. Female BALB/c mice were inoculated with 4T1 breast cancer cells and treatment with DE-EDCP started five days following orthotopic tumor implantation. The frequency and phenotype of tumor-infiltrating natural killer (NK) and natural killer T (NKT) cells were analyzed by flow cytometry. Results. DE-EDCP inhibited migratory potential of highly metastatic 4T1 cells. DE-EDCP facilitated accumulation of CD3+CD49+ NKT cells and CD3-CD49+ NK cells in tumor microenvironment. DE-EDCP treatment led to significant decrement of tumor infiltrating anergic NKT cells expressing cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), killer cell lectin like receptor G1 (KLRG-1) and programmed cell death protein-1 (PD-1). Mice given DE-EDCP had significantly increased percentages of tumoricidal fas ligand (FasL) positive NK cells. Conclusion. DE-EDCP inhibits murine breast cancer progression through direct effects on tumor cells and by facilitating anti-tumor immunity. DE-EDCP enhances accumulation, promotes tumoricidal phenotype and maintenances responsiveness of NK and NKT cells in 4T1 murine breast cancer

Attenuation of NK cells facilitates mammary tumor growth in streptozotocin-induced diabetes in mice

© 2018 Society for Endocrinology. Diabetic patients have higher incidence and mortality of cancer. Recent study revealed that hyperglycemia-induced oxidative stress is involved in the acceleration of tumor metastasis. We used model of high-dose streptozotocin-induced diabetes to investigate its effect on tumor growth and modulation of antitumor immune response of 4T1 murine breast cancer in BALB/c mice. Diabetes accelerated tumor appearance, growth and weight, which was associated with decreased NK cells cytotoxicity against 4T1 tumor cells in vitro. Diabetes reduced frequencies of systemic NKG2D+, perforin+, granzyme+, IFN-γ+ and IL-17+ NK cells, while increased level of PD-1 expression and production of IL-10 in NK cells. Diabetes decreased percentage of NKG2D+NK cells and increased percentage of PD-1+ NK cells also in primary tumor. Diabetes increased accumulation of IL-10+ Tregs and TGF-β + myeloid-derived suppressor cells (MDSCs) in spleen and tumor. Diabetic sera in vitro significantly increased the percentage of KLRG-1+ and PD-1+ NK cells, decreased the percentage of IFN-γ+NK cells, expression of NKp46 and production of perforin, granzyme, CD107a and IL-17 per NK cell in comparison to glucose-added mouse sera and control sera. Significantly increased percentages of inducible nitric oxide synthase (iNOS) and indoleamine 2,3-dioxygenase (IDO) producing MDSCs and dendritic cells (DC) were found in the spleens of diabetic mice prior to tumor induction. 1-methyl-DL-tryptophan, specific IDO inhibitor, almost completely restored phenotype of NK cells cultivated in diabetic sera. These findings indicate that diabetes promotes breast cancer growth at least in part through increased accumulation of immunosuppressive cells and IDO-mediated attenuation of NK cells

Fecal sST2 correlates with the disease severity of ulcerative colitis

© 2019 Inst. Sci. inf., Univ. Defence in Belgrade. All rights reserved. Background/Aim. Ulcerative colitis (UC) is a chronic, relapsing inflammatory disease affecting the distal colon and rectum with complex pathogenesis and diagnosis, indicating the need for new diagnostic and prognostic markers. The aim of this study was to determine the fecal values of TNF-α, IL-17, IL-10 and soluble protein ST2 (sST2) in the patients with UC and their relationship with clinicopathological aspects. Methods. The samples of stool of 80 patients with UC were analyzed. Concentrations of TNF-α, IL-17, IL-10 and sST2 were measured by ELISA. Results. Concentrations of TNF-α, IL-17 and sST2 were significantly increased in the feces of patients with the higher endoscopic, clinical and total Mayo score, as well as in the patients with an intense crypt destruction, erosion of the mucous membranes, architectural changes, neutrophil infiltration and eosinophil infiltration. The local value of anti-inflammatory cytokine IL-10 in liquid fraction of feces was increased in the patients with an advanced endoscopic stage of UC. The moderate positive correlation between the fecal sST2/IL-17 and the clinical and histological parameters of disease severity and also the strong correlation between sST2 and IL-17 was also observed in the feces of patients with UC. The analysis of receiver operating characteristic (ROC) curves showed that the optimal cut-off value for sST2 of 624.0 pg/g allows the discrimination of clinical stages of UC. Conclusion. The increased fecal value of sST2 in the UC patients with a higher endoscopic, clinical and histological stage of disease may be considered as a sign of the disease severity. The fecal values of sST2 can be used as a valuable marker for UC severity

Tgf-Β as a marker of ulcerative colitis and disease severity

© 2018, University of Kragujevac, Faculty of Science. All rights reserved. Ulcerative colitis (UC) represents chronic inflammation of the large intestine. Immune response plays an important role in disease genesis and progression. Activated leukocytes secrete several cytokines that actively regulate the inflammatory response in UC. The aim of this study was to determine levels of cytokines IL-17, IL-27, IFN-γ and TGF-β in patients with UC and to test them as biomarkers for disease. The blood samples of 24 patients with ulcerative colitis without previous treatment and 37 healthy individuals were analyzed. Serum levels of IL-17, IL-27, IFN-γ and TGF-β were measured using sensitive enzyme-linked immunosorbent assay (ELISA) kits. Serum levels of IL-17, IL-27, IFN-γ and TGF-β were increased in patients with UC, compared to healthy controls (p=0.022; p=0.001; p=0.001; and p=0.002; respectively). Ratios of cytokines IL-27/IL-17, IFN-γ/TGF-β and IL-17/TGF-β were significantly higher in group of patients with UC (p=0.002; p=0.002; p=0.003; respectively). Serum value of TGF-β higher than 20 pg/ml presents a highly sensitive and specific marker for UC. We believe that increased production and predominance of immunosupressive TGF-β may represent compensatory mechanism for ongoing pro-inflammatory processes in UC

Innate lymphoid cells: Roles in tumour genesis and progression

© 2015 University of Kragujevac, Faculty of Science. All rights reserved. Innate lymphoid cells (ILCs) represent the most recently identified members of the innate immune system. These cells play important roles in inflammation, tissue remodelling and metabolic disease. ILCs can be subdivided into three major groups according to their cytokine production. The role of ILCs in tumourigenesis and tumour progression is not completely clarified. In this review, we discuss whether and how ILCs are involved in tumour genesis, growth and metastasis