scholarly journals Decidual NK cell-derived conditioned medium from miscarriages affects endometrial stromal cell decidualisation: endocannabinoid anandamide and tumour necrosis factor-α crosstalk

2020 ◽  
Vol 35 (2) ◽  
pp. 265-274 ◽  
Author(s):  
B M Fonseca ◽  
S C Cunha ◽  
D Gonçalves ◽  
A Mendes ◽  
J Braga ◽  
...  
Keyword(s):  
Conditioned Medium ◽  
Stromal Cell ◽  
First Trimester ◽  
Cytokine Profile ◽  
Enzyme Linked Immunosorbent Assay ◽  
Endometrial Stromal Cell ◽  
Unk Cells ◽  
Tnf Α ◽  
The Impact ◽  
Unk Cell

Abstract STUDY QUESTION What are the effects of endocannabinoid anandamide (AEA) in uterine natural killer (unK) cells from miscarriage decidua, regarding their cytokine profile and endometrial stromal cell (ESC) crosstalk? SUMMARY ANSWER uNK-conditioned media from miscarriage samples present high TNF-α levels which inhibit ESC decidualisation. WHAT IS KNOWN ALREADY AEA plasma levels are higher in women who have suffered a miscarriage. Moreover, AEA inhibits ESC proliferation and differentiation, although the levels and impact on the uNK cell cytokine profile at the feto-maternal interface remain elusive. STUDY DESIGN, SIZE, DURATION This laboratory-based study used human primary uNK cells which were isolated from first-trimester decidua (gestational age, 5–12 weeks) derived from 8 women with elective pregnancy termination and 18 women who suffered a miscarriage. PARTICIPANTS/MATERIALS, SETTING, METHODS The first-trimester placental tissues were assayed for AEA levels by UPLC-MS/MS and respective enzymatic profile by western blot. The uNK cells were isolated and maintained in culture. The expression of angiogenic markers in uNK cells was examined by quantitative PCR (qPCR). The uNK-conditioned medium was analysed for IFN-γ, TNF-α and IL-10 production by enzyme-linked immunosorbent assay, and the impact on ESC differentiation was assessed by measuring decidual markers Prl, Igfbp-1 and Fox01 mRNA expression using qPCR. MAIN RESULTS AND THE ROLE OF CHANCE AEA levels were higher in miscarriage decidua compared with decidua from elective terminations. The uNK cell-conditioned medium from the miscarriage samples exhibited high TNF-α levels and interfered with the decidualisation of ESCs. Exacerbated inflammation and elevated TNF-α levels at the feto-maternal interface may trigger AEA signalling pathways that, in turn, may impact decidualisation and the angiogenic ability of uNK cells. LARGE-SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION Primary uNK cell responses are based on a simple in vitro model. Thus, in complex microenvironments, such as the feto-maternal interface, the mechanisms may not be exactly the same. Also, the inflammatory events of miscarriage that, in this study, have happened prior to processing of the samples may cause different responses to that observed. In addition, the magnitude of the inflammatory response, required to trigger the AEA pathways that impact decidualisation and the uNK angiogenic ability in vivo, is still unclear. WIDER IMPLICATIONS OF THE FINDINGS The endocannabinoid AEA is a modulator of reproductive competence. AEA not only may contribute to neuroendocrine homeostasis but also can take part in uterine changes occurring during early pregnancy. STUDY FUNDING/COMPETING INTEREST(S) The work was supported by UID/MULTI/04378/2019 with funding from Fundação para a Ciência e a Tecnologia (FCT)/MCTES through national funds and PORTUGAL 2020 Partnership Agreement, NORTE-01-0145-FEDER-000024. S.C. Cunha acknowledges FCT for the IF/01616/2015 contract. There are no conflicts of interest.

scholarly journals 270.Macrophage inhibitory cytokine-1 at the maternal - fetal interface in early pregnancy

2004 ◽  
Vol 16 (9) ◽  
pp. 270 ◽  
Author(s):  
B. Marjono ◽  
U. Manuelpillai ◽  
E. Dimitriadis ◽  
L. Salamonsen ◽  
S. Breit ◽  
...  
Keyword(s):  
Early Pregnancy ◽  
Human Placenta ◽  
Stromal Cell ◽  
First Trimester ◽  
Matrix Metalloproteinase 2 ◽  
Plasminogen Activation ◽  
Endometrial Stromal Cell ◽  
Tnf Α ◽  
Pai 1

Macrophage inhibitory cytokine-1 (MIC-1) is a transforming growth factor-β (TGF-β) superfamily member, first isolated from activated macrophages and subsequently localised in the human placenta. We previously reported that decreased circulating levels in very early pregnancy are associated with subsequent miscarriage. We undertook these current in vitro studies to investigate possible roles for MIC-1 in early pregnancy: (1) regulation of placental matrix metalloproteinase-2 and -9 (MMP-2 and -9); (2) effect on placental apoptosis; and (3) regulation of endometrial stromal cell decidualisation. (1) First trimester placental explant cultures were treated with 100–200 ng/mL MIC-1 � 1/1000 (v/v) anti-MIC-1 antibody. MMP-2 and -9 were measured by gelatin zymography. MMP activation via the plasminogen activation pathway was examined by measuring mRNA expression for urokinase plasminogen activator and its receptor (uPA, uPAR) and type-1 plasminogen activation inhibitor (PAI-1). (2) In first trimester trophoblast explants, apoptosis was induced in vitro with tumor necrosis factor-α (TNF-α) and interferon-β (IFN-β) � 200 ng/mL MIC-1. The pro-apoptosis factor caspase-3 was localised by immunohistochemistry. (3) Using an established model of oestrogen and progesterone induced endometrial stromal cell decidualisation, MIC-1 production was measured and correlated with morphological changes. Cultures were also treated with 20 ng/mL MIC-1. MIC-1 treatment inhibited activation of both MMP-2 and MMP-9 while treatment with anti-MIC-1 antibody blocked the inhibition. uPA, uPAR and PAI-1 mRNA did not change with either treatment. MIC-1 treatment mitigated TNF-α/IFN-β induced trophoblast apoptosis. MIC-1 production increased during induced decidualisation and MIC-1 treatment facilitates further decidualisation in this model. MIC-1 appears to have a number of potentially important functions in the human placenta and decidua consistent with physiological roles in normal placentation. Whether these functions are key to successful pregnancy remains to be studied.

scholarly journals The Role of TNF-α and Anti-TNF-α Agents during Preconception, Pregnancy, and Breastfeeding

2021 ◽  
Vol 22 (6) ◽  
pp. 2922
Author(s):  
Katarzyna Romanowska-Próchnicka ◽  
Anna Felis-Giemza ◽  
Marzena Olesińska ◽  
Piotr Wojdasiewicz ◽  
Agnieszka Paradowska-Gorycka ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
First Trimester ◽  
Endocrine Function ◽  
Necrosis Factor Alpha ◽  
Hormone Synthesis ◽  
Migratory Activity ◽  
Immune System Diseases ◽  
Tnf Α ◽  
The Impact ◽  
In Pregnancy

Tumor necrosis factor-alpha (TNF-α) is a multifunctional Th1 cytokine and one of the most important inflammatory cytokines. In pregnancy, TNF-α influences hormone synthesis, placental architecture, and embryonic development. It was also shown that increased levels of TNF-α are associated with pregnancy loss and preeclampsia. Increased TNF-α levels in complicated pregnancy draw attention to trophoblast biology, especially migratory activity, syncytialisation, and endocrine function. Additionally, elevated TNF-α levels may affect the maternal-fetal relationship by altering the secretory profile of placental immunomodulatory factors, which in turn affects maternal immune cells. There is growing evidence that metabolic/pro-inflammatory cytokines can program early placental functions and growth in the first trimester of pregnancy. Furthermore, early pregnancy placenta has a direct impact on fetal development and maternal immune system diseases that release inflammatory (e.g., TNF-α) and immunomodulatory factors, such as chronic inflammatory rheumatic, gastroenterological, or dermatological diseases, and may result in an abnormal release of cytokines and chemokines in syncytiotrophoblasts. Pregnancy poses a challenge in the treatment of chronic disease in patients who plan to have children. The activity of the disease, the impact of pregnancy on the course of the disease, and the safety of pharmacotherapy, including anti-rheumatic agents, in pregnancy should be considered.

scholarly journals Proliferation of Uterine Natural Killer Cells Is Induced by Human Chorionic Gonadotropin and Mediated via the Mannose Receptor

Endocrinology ◽  
2009 ◽  
Vol 150 (6) ◽  
pp. 2882-2888 ◽  
Author(s):  
Nicole Kane ◽  
Rodney Kelly ◽  
Philippa T. K. Saunders ◽  
Hilary O. D. Critchley
Keyword(s):  
Natural Killer ◽  
Mannose Receptor ◽  
Lh Receptor ◽  
Uterine Natural Killer Cells ◽  
Unk Cells ◽  
The Impact ◽  
Insight Into ◽  
Unk Cell ◽  
Uterine Natural Killer

The endometrial lining of the human uterus contains a population of phenotypically distinct (CD56bright, CD16dim), tissue-specific, natural killer [uterine natural killer (uNK)] cells that play a key role in the establishment of a successful pregnancy. An increase in the number of endometrial uNK cells occurs when the conceptus implants, and there is a further increase during the early stages of placentation. Here, we describe studies that have identified human chorionic gonadotrophin (hCG), a glycoprotein synthesized by the preimplantation conceptus, as a novel regulator of uNK cell proliferation. The impact of hCG on uNK cells was mediated via the mannose receptor (CD206) rather than by the classical hCG/LH receptor that was not expressed. The mannose receptor and hCG were colocalized on the surface of uNK cells, and proliferation did not occur if cells were incubated with deglycosylated hCG or intact hCG in the presence of excess d-Mannose. These novel observations provide new insight into the endocrine-immune dialogue that exists between the conceptus and immune cells within the receptive endometrium, and have implications for the role of uNK cell-trophoblast interactions and pregnancy outcome.

scholarly journals Cytokine profile of Ehrlich ascites tumor treated withBothrops jararacavenom

2002 ◽  
Vol 11 (4) ◽  
pp. 197-201 ◽  
Author(s):  
Reinaldo J. da Silva ◽  
Márcia G. da Silva ◽  
Lízia C. Vilela ◽  
Denise Fecchio
Keyword(s):  
Tumor Growth ◽  
Antitumor Effect ◽  
Cytokine Profile ◽  
Ehrlich Ascites Tumor ◽  
Enzyme Linked Immunosorbent Assay ◽  
Ascites Tumor ◽  
Ehrlich Ascites ◽  
Tnf Α ◽  
Cytokine Levels ◽  
Eat Cells

We previously demonstrated thatBothrops jararacavenom (BjV) has an antitumor effect on Ehrlich ascites tumor (EAT) cells and induces an increase of polymorphonuclear leukocytes in early stages of tumor growth. It has been reported that this venom presents an important inflammatory effect when inoculated in animal models and in human snakebites, and that cytokine levels have been detected in these cases. To evaluate whether the cytokines can be involved with the suppression of the tumoral growth, we evaluate the cytokine profile in the peritoneal cavity of mice inoculated with EAT cells and treated withBjV. Swiss mice were inoculated with EAT cells by the intraperitoneal route and treated withBjV venom (0.4 mg/kg, intraperitoneally), on the 1st, 4th, 7th, 10th, and 13th day. Mice were evaluated for cytokine levels on the 2nd, 5th, 8th, 11th and 14th day. Analysis was performed using an enzyme-linked immunosorbent assay for interleukin (IL)-1α, IL-2, IL-4, IL-6, IL-10, IL-13, and tumor necrosis factor-α (TNF-α) levels in the peritoneal washing supernatant. Results were analyzed statistically by the Kruskal-Wallis and Dunn's tests at the 5% level of significance. We observed that EAT implantation induces IL-6 production on the 11th and 14th days of tumor growth, IL-10 on the 11th day and TNF-α on the 14th day. The treatment withBjV suppresses production of these cytokines. In addition, IL-13 was produced by animals that were inoculated only with venom on the 11th and 14th days, and by the group inoculated with EAT cells and treated with venom on the 2nd and 14th days. Furthermore, we suggest that the IL-6 detected in the present study is produced by the EAT cells and the suppression of its production could be associated with the antitumor effect ofBjV.

scholarly journals Characterization of the Plasmacytoid Dendritic Cell Response to Transmitted/Founder and Nontransmitted Variants of HIV-1

2018 ◽  
Vol 92 (19) ◽  
Author(s):  
Jordan Ari Schwartz ◽  
Hongliang Zhang ◽  
Zachary Ende ◽  
Martin J. Deymier ◽  
Terry Lee ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Plasmacytoid Dendritic Cell ◽  
Female Genital Tract ◽  
Enzyme Linked Immunosorbent Assay ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
The Impact ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) infection often arises from a single transmitted/founder (TF) viral variant among a large pool of viruses in the quasispecies in the transmitting partner. TF variants are typically nondominant in blood and genital secretions, indicating that they have unique traits. The plasmacytoid dendritic cell (pDC) is the primary alpha interferon (IFN-α)-producing cell in response to viral infections and is rapidly recruited to the female genital tract upon exposure to HIV-1. The impact of pDCs on transmission is unknown. We investigated whether evasion of pDC responses is a trait of TF viruses. pDCs from healthy donors were stimulated in vitro with a panel of 20 HIV-1 variants, consisting of one TF variant and three nontransmitted (NT) variants each from five transmission-linked donor pairs, and secretion of IFN-α and tumor necrosis factor alpha (TNF-α) was measured by enzyme-linked immunosorbent assay (ELISA). No significant differences in cytokine secretion in response to TF and NT viruses were observed, despite a trend toward enhanced IFN-α and TNF-α production in response to TF viruses. NT viruses demonstrated polarization toward production of either IFN-α or TNF-α, indicating possible dysregulation. Also, for NT viruses, IFN-α secretion was associated with increased resistance of the virus to inactivation by IFN-α in vitro, suggesting in vivo evolution. Thus, TF viruses do not appear to preferentially subvert pDC activation compared to that with nontransmitted HIV-1 variants. pDCs may, however, contribute to the in vivo evolution of HIV-1. IMPORTANCE The plasmacytoid dendritic cell (pDC) is the first cell type recruited to the site of HIV-1 exposure; however, its contribution to the viral bottleneck in HIV-1 transmission has not been explored previously. We hypothesized that transmitted/founder viruses are able to avoid the pDC response. In this study, we used previously established donor pair-linked transmitted/founder and nontransmitted (or chronic) variants of HIV-1 to stimulate pDCs. Transmitted/founder HIV-1, instead of suppressing pDC responses, induced IFN-α and TNF-α secretion to levels comparable to those induced by viruses from the transmitting partner. We noted several unique traits of chronic viruses, including polarization between IFN-α and TNF-α production as well as a strong relationship between IFN-α secretion and the resistance of the virus to neutralization. These data rule out the possibility that TF viruses preferentially suppress pDCs in comparison to the pDC response to nontransmitted HIV variants. pDCs may, however, be important drivers of viral evolution in vivo.

scholarly journals Early macrophage infiltrates impair pancreatic cancer cell growth by TNF-α secretion

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Cansu Tekin ◽  
Hella L. Aberson ◽  
Maarten F. Bijlsma ◽  
C. Arnold Spek
Keyword(s):  
Cell Death ◽  
Conditioned Medium ◽  
Cell Lines ◽  
Annexin V ◽  
Therapeutic Benefit ◽  
Ductal Adenocarcinoma ◽  
Potential Candidate ◽  
Tnf Α ◽  
The Impact

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a grim disease with high mortality rates. Increased macrophage influx in PDAC is a common hallmark and associated with poor prognosis. Macrophages have high cellular plasticity, which can differentiate into both anti- and pro-tumorigenic properties. Here, we investigated how naïve (M0) macrophages differ from other macrophages in their anti-tumorigenic activities. Methods In vitro BrdU proliferation and Annexin V cell death analyses were performed on PANC-1 and MIA PaCa-2 PDAC cell lines exposed to conditioned medium of different macrophage subsets. Macrophage secreted factors were measured by transcript analysis and ELISA. Therapeutic antibodies were used to functionally establish the impact of the identified cytokine on PDAC proliferation. Results Proliferation and cell death assays revealed that only M0 macrophages harbor anti-tumorigenic activities and that M1, M2, and TAMs do not. mRNA analysis and ELISA results suggested TNF-α as a potential candidate to mediate M0 macrophage induced cell death. To demonstrate the importance of TNF-α in M0 macrophage-induced cell death, PANC-1 and MIA PaCa-2 cell-lines were exposed to M0 macrophage conditioned medium in the presence of the TNF-α inhibitor Infliximab, which effectively diminished the anti-tumor activities of M0 macrophages. Conclusion Newly tumor-infiltrated naive M0 macrophages exert anti-tumorigenic activities via TNF-α secretion. Their subsequent differentiation into either M1, M2, or TAM subsets reduces TNF-α levels, thereby abolishing their cytotoxic activity on PDAC cells. These data suggest that reestablishing TNF-α secretion in differentiated macrophages might yield a therapeutic benefit.

scholarly journals TNFR, TRAF2, NF-κB mRNA Levels of Glioblastoma Multiforme Cells Treated by Conditioned Medium of Umbilical Cord-derived Mesenchymal Stem Cells

2019 ◽  
Vol 11 (2) ◽  
pp. 217-24
Author(s):  
Novi Silvia Hardiany ◽  
Yohana Yohana ◽  
Septelia Inawati Wanandi
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Glioblastoma Multiforme ◽  
Conditioned Medium ◽  
Signaling Pathway ◽  
Umbilical Cord ◽  
Protein Level ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tnf Α ◽  
Α Level

BACKGROUND: Glioblastoma multiforme (GBM) is a human malignant brain tumor which is arise from glial cells. Our previous study proved that GBM cells proliferation increased after treating by conditioned medium of umbilical cord-derived mesenchymal stem cells (CM-UCSCs). Cells proliferation is probably mediated by tumor necrosis factor (TNF)-α which could bind to membrane receptor and induce signaling pathway. Therefore, this research was intended to analyze the mRNA expression of TNF-α signaling pathway molecules on CM-treated GBM cells by measuring TNF receptor 1 and 2 (TNFR1 and TNFR2), TNFR associated factor 2 (TRAF2), nuclear factor kappa B (NF-κB) mRNA level, and TNFR2 protein level.METHODS: UCSCs and human glioblastoma T98G cells were cultured and harvested after 80% confluence. CM was prepared by growing UCSCs in serum alpha Minimum Essential Media (α-MEM) for 24 hours. Fifty percent concentration of CM-UCSCs was used to treat T98G cells for 24 hours. TNF-α level in CM-UCSC was detected using enzyme linked-immunosorbent assay (ELISA), while the expression of TNFR1, TNFR2, TRAF2 and NF-κB were detected using quantitative Reverse Transcriptase Polymerase Chain Reaction (qRT-PCR), and TNFR2 protein level was detected using sandwich ELISA.RESULTS: TNF-α level was detected in CM-UCSCs 4.4 pg/mL. Moreover, the expression of TNFR1, TNFR2, TRAF2 and NF-κB were significantly 1.4-fold, 4.9-fold, 5.6-fold, 1.8-fold respectively higher in T98G treated cells than control. TNFR2 protein level in T98G treated cells was 11.57 pg/mg protein higher than control.CONCLUSION: The expression of molecules involved in TNF-α signaling pathway were up regulated in T98G cells treated by CM-UCSCs.KEYWORDS: CM-UCSCs, TNFR1, TNFR2, TRAF2, NF-κB, T98G cells

scholarly journals Early macrophage infiltrates impair pancreatic cancer cell growth by TNF-α secretion

2020 ◽  
Author(s):  
Cansu Tekin ◽  
Hella L Aberson ◽  
Maarten F Bijlsma ◽  
C. Arnold Spek
Keyword(s):  
Cell Death ◽  
Conditioned Medium ◽  
Cell Lines ◽  
Annexin V ◽  
Therapeutic Benefit ◽  
Ductal Adenocarcinoma ◽  
Potential Candidate ◽  
Tnf Α ◽  
The Impact

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is a grim disease with high mortality rates. Increased macrophage influx in PDAC is a common hallmark and associated with poor prognosis. Macrophages have high cellular plasticity, which can differentiate into both anti- and pro-tumorigenic properties. Here, we investigated how naïve (M0) macrophages differ from other macrophages in their anti-tumorigenic activities.Methods: In vitro BrdU proliferation and Annexin V cell death analyses were performed on PANC-1 and MIA PaCa-2 PDAC cell lines exposed to conditioned medium of different macrophage subsets. Macrophage secreted factors were measured by transcript analysis and ELISA. Therapeutic antibodies were used to functionally establish the impact of the identified cytokine on PDAC proliferation.Results: Proliferation and cell death assays revealed that only M0 macrophages harbor anti-tumorigenic activities and that M1, M2, and TAMs do not. mRNA analysis and ELISA results suggested TNF-α as a potential candidate to mediate M macrophage induced cell death. To demonstrate the importance of TNF-α in M macrophage-induced cell death, PANC-1 and MIA PaCa-2 cell-lines were exposed to M macrophage conditioned medium in the presence of the TNF-α inhibitor Infliximab, which effectively diminished the anti-tumor activities of M0 macrophages.Conclusion: Newly tumor-infiltrated naive M0 macrophages exert anti-tumorigenic activities via TNF-α secretion. Their subsequent differentiation into either M1, M2, or TAM subsets reduces TNF-α levels, thereby abolishing their cytotoxic activity on PDAC cells. These data suggest that reestablishing TNF-α secretion in differentiated macrophages might yield a therapeutic benefit.

scholarly journals Gender features of the cytokine profile in patients with chronic atrophic gastritis

2021 ◽  
Vol 55 (4) ◽  
pp. 217-222
Author(s):  
L.M. Mosiychuk ◽  
O.M. Tatarchuk ◽  
O.P. Petishko
Keyword(s):  
Atrophic Gastritis ◽  
Structural Changes ◽  
Chronic Atrophic Gastritis ◽  
Cytokine Profile ◽  
Dynamic Monitoring ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha

Background. Сhronic atrophic gastritis certainly remains an urgent problem of gastroenterology but data on sexual differences in the content of cytokines in this pathology are quite contradictory. The purpose of the study: to assess the gender chara­cteristics of the cytokine profile in patients with chronic atrophic gastritis. Materials and methods. The study included 120 patients with gastric atrophy, according to histological examination of biop­sies. The control group consisted of 20 healthy individuals, men and women equally. In all patients, we have evaluated the levels of interleukins (IL-8, IL-10, IL-18), tumor necrosis factor alpha (TNF-α), vasculoendothelial growth factor (VEGF) by enzyme-linked immunosorbent assay using appropriate reagent from Vector-BEST kits and the Stat Fax 303 Plus analyzer. Results. In men with chronic atrophic gastritis, there is a more pronounced imba­lance towards pro-inflammatory cytokines, in particular the level of IL-18 is 1.7 times higher (p < 0.05) than in women. In 46.2 % of cases, the content of IL-8 was also elevated in men by 1.3 times (p > 0.05) compared to women. The level of anti-inflammatory cytokine IL-10 does not have a significant gender difference in patients with precancerous conditions of the stomach. The median of IL-18/IL-10 ratio in men is 2 times higher than in women: 65.36 (21.67; 154.25) vs. 32.15 (12.76; 191.85) (p < 0. 05). In males, IL-8/IL-10 ratio is also 1.5 times higher, which is 2.25 (1.29; 7.68) vs. 1.49 (0.75; 9.78) but this difference was not statically significant. Serum content of VEGF in men exceeded the same indicator in women by 1.4 times (p < 0.05). Direct correlation between VEGF content and the levels of TNF-α (r = 0.47, p < 0.05), IL-8 (r = 0.42, p < 0.05), IL-18 (r = 0.58, p < 0.05) confirm the evidence of increased VEGF expression under the influence of many proangiogenic growth factors and proinflammatory cytokines. Conclusions. With an increase in the level of IL-18 and VEGF by more than 30 %, men require dynamic monitoring for early detection of precancerous structural changes in the gastric mucosa.

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