| tumor necrosis factor | OKDB#: 2351 |
| Symbols: | TNF | Species: | human | ||
| Synonyms: | DIF, TNFA, TNFSF2, TNLG1F, TNF-alpha | Locus: | 6p21.33 in Homo sapiens |
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| General Comment | NCBI Summary: This gene encodes a multifunctional proinflammatory cytokine that belongs to the tumor necrosis factor (TNF) superfamily. This cytokine is mainly secreted by macrophages. It can bind to, and thus functions through its receptors TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. This cytokine is involved in the regulation of a wide spectrum of biological processes including cell proliferation, differentiation, apoptosis, lipid metabolism, and coagulation. This cytokine has been implicated in a variety of diseases, including autoimmune diseases, insulin resistance, psoriasis, rheumatoid arthritis ankylosing spondylitis, tuberculosis, autosomal dominant polycystic kidney disease, and cancer. Mutations in this gene affect susceptibility to cerebral malaria, septic shock, and Alzheimer disease. Knockout studies in mice also suggested the neuroprotective function of this cytokine. [provided by RefSeq, Aug 2020] | ||||
| General function | Ligand, Cytokine, Cell death/survival, Apoptosis | ||||
| Comment | TNF-α Suppressed FSH-Induced LH Receptor Expression Through Transcriptional Regulation in Rat Granulosa Cells. Nakao K et al. (2015) Several inflammatory cytokines regulate ovarian function. TNF-α is produced in granulosa cells (GCs) under physiological conditions and have a reciprocal action on follicle development. By contrast, in pelvic inflammatory diseases, TNF-α is excessively produced in the pelvic cavity and has an adverse effect on reproductive functions. The objective of this study was to elucidate the mechanism of action of TNF-α on the expression of LH receptor (LHR) in immature rat GCs. TNF-α suppressed FSH-induced LHR mRNA and protein expression and was not associated with cAMP accumulation. Using a luciferase assay, the construct containing base pairs -1389 to -1 of the rat Lhcgr promoter revealed that TNF-α decreased FSH-induced promoter activity. In response to TNF-α, nuclear factor (NF)-κB p65 was translocated to the nucleus, and the suppressive effect of TNF-α on LHR mRNA expression was abrogated by NF-κB inhibitor. In a chromatin immunoprecipitation assay, TNF-α induced the association of NF-κB p65 with the rat Lhcgr transcriptional promoter region. NF-κB p65 and histone deacetylase (HDAC) interact to mediate expression of several genes at a transcriptional level. HDAC activity is thought to induce tight connections within local chromatin structures and repress gene transcription. Furthermore, the TNF-α-induced suppression of LHR mRNA expression was blocked by an HDAC inhibitor. Taken together, these results suggest that the interaction of NF-κB p65 with HDAC in the promoter region of rat Lhcgr might be responsible for TNF-α action on the regulation of LHR.////////////////// Morrison LJ, et al. found that tumor necrosis factor alpha enhances oocyte/follicle apoptosis in the neonatal rat ovary.Sasson R, et al.found dexamethasone (Dex) and hydrocortisone efficiently suppressed TNF alpha-induced apoptosis in granulosa cells. TNF alpha dramatically reduced intracellular levels of Bcl-2, while Dex abrogated this reduction. TNF alpha reduced considerably intracellular levels of StAR protein, a key regulating factor in steroidogenesis. This reduction can be explained only in part by elimination of cells through apoptosis, since loss of steroidogenic capacity was much higher and faster than the rate and extent of loss of cell viability induced by TNF alpha, suggesting independent mechanisms for TNF alpha-induction of apoptosis and TNF alpha-suppression of steroidogenesis. | ||||
| Cellular localization | |||||
| Comment | family123 | ||||
| Ovarian function | Follicle endowment, Follicle development, Preantral follicle growth, Steroid metabolism, Luteolysis, Oocyte maturation | ||||
| Comment | Effects of tumour necrosis factor-alpha and interleukin-1 beta on in vitro development of bovine secondary follicles. Paulino LRFM et al. (2018) The objective of this study was to determine the effects of TNF-α and IL-1β on development and survival of bovine secondary follicle culture in vitro for 18 days. Secondary follicles (~0.2 mm) were isolated from ovarian cortex and individually cultured at 38.5°C, with 5% CO2 in air, for 18 days, in TCM-199+ alone (cultured control) or supplemented with 10 ng/ml IL-1β, 10 ng/ml TNF-α or both TNF-α and IL-1β. The effects of these treatments on growth, follicular survival, antrum formation, viability, ultrastructure and mRNA levels for GDF-9, c-MOS, H1foo and Cyclin B1 were evaluated. The results showed that addition of TNF-α to culture medium increased follicular diameter and rate of antrum formation, whereas that of IL-1β and a mixture of IL-1β and TNF-α did not do so. Ultrastructural analysis showed that, among the tested cytokine treatments, follicles cultured in the presence of TNF-α had the best-preserved oocytes and granulosa cells. The presence of TNF-α, IL-1β or both did not influence the expression of mRNAs analysed. In conclusion, in contrast to IL-1β, TNF-α promotes growth of and antrum formation in in vitro cultured bovine secondary follicles, while their ultrastructure and viability were maintained.////////////////// Identification of developmental competence-related genes in mature porcine oocytes. Yuan Y et al. Oocyte competence is a key factor limiting female fertility, yet the underlying molecular mechanisms that contribute to oocyte competence remain unclear. The objective of this study was to elucidate specific genes whose function contributes to oocyte competence. We observed that 6 of 20 target genes examined were differentially expressed between adult (more competent) and prepubertal (less competent) porcine in vitro matured (IVM) oocytes. These genes were the cholesterol synthesis-related gene HMG-CoA reductase (HMGCR), fatty acid oxidation genes acyl-CoA synthetase long-chain family member 3 (ACSL3) and long-chain acyl-CoA dehydrogenase (ACADL), glycolytic genes fructose 1,6 bisphosphate aldolase (ALDOA) and lactate dehydrogenase C (LDHC), and tumor necrosis factor-a (TNF). These 6 genes, as well as 3 other genes porcine endogenous retrovirus (PERV), transcribed loci 10 (TL10), serine/arginine-rich splicing factor 1 (SRSF1), were further analyzed by comparing transcript abundance in IVM and in vivo matured (VVM) prepubertal and adult porcine oocytes. Among these 9 target genes, 5 were differentially expressed between IVM and VVM prepubertal oocytes, while 8 genes were differentially expressed between IVM and VVM adult oocytes. No genes were differentially expressed between VVM prepubertal and adult oocytes. A functional study of TNF demonstrated that depletion of endogenous TNF decreased oocyte competence and TNFAIP6 expression in cumulus cells, while TNF in IVM medium regulated TNFAIP6 expression in cumulus cells. Differential expression of the genes identified in this study suggests that these genes may be functionally relevant to oocyte competence. Mol. Reprod. Dev. ? 2011 Wiley-Liss, Inc. ///////Evaluation of the Pro-inflammatory Cytokine Tumor Necrosis Factor-a in Adolescents with Polycystic Ovary Syndrome. [Pawelczak M 2014 et al. BACKGROUND Patients with polycystic ovary syndrome (PCOS) often suffer from comorbidities associated with chronic inflammation characterized by elevations in pro-inflammatory cytokines. There is limited data on markers of chronic inflammation, in particular Tumor Necrosis Factor-alpha (TNF-a), in adolescents with PCOS. OBJECTIVES To compare serum levels of TNF-a in overweight or obese adolescents with PCOS and obese controls. In the PCOS group, to correlate serum TNF-a levels with body mass index (BMI) z-score, severity of hyperandrogenism, degree of insulin resistance, and ovarian ultrasonographic characteristics. METHODS We performed a cross-sectional retrospective analysis of clinical and biochemical findings in 23 overweight or obese adolescent females with PCOS (mean BMI z-score 2, mean age 15.2 yrs) and 12 obese age- and sex-matched controls (mean BMI z-score 2, mean age 14.1 y). All subjects were post-menarchal. Serum TNF-a levels were compared between groups. In the PCOS group, cytokine levels were correlated with BMI z-score, androgen levels, fasting insulin and glucose levels as well as ovarian ultrasonographic features. RESULTS Both groups were comparable in age, BMI z-score, fasting glucose, and fasting insulin. Mean free testosterone was 9.76 5.13 pg/mL in the PCOS group versus 5 2.02 pg/mL in the control group (P = .0092). Serum TNF-a was 7.4 4 pg/mL in the PCOS group versus 4.8 3.16 pg/mL in the control group (P = .0468). There was no significant correlation between serum TNF-a and BMI z-score, free testosterone, fasting insulin, or fasting glucose. No correlation existed between serum TNF-a and ovarian follicle number, distribution, or volume. CONCLUSIONS Serum TNF-a is elevated in overweight/obese adolescents with PCOS. Chronic inflammation in adolescents with PCOS render them at a potential increased risk for the development of atherosclerosis, type 2 diabetes, cancer, infertility, and other comorbidities. Every effort should be made to identify adolescents with PCOS early and initiate aggressive therapy to prevent future complications. /////////////////////////Tumor necrosis factor alpha inhibits ovulation and induces granulosa cell death in rat ovaries. Yamamoto Y et al. (2015) We evaluated the role of tumor necrosis factor alpha (TNFα) in rat ovulation and granulosa cell death of ovarian follicles during the periovulatory stage. Immature rats primed with pregnant mare serum gonadotropin were injected intraperitoneally with human chorionic gonadotropin (hCG), and TNFα was injected into the bursa 48 h later. The total number of released oocytes was counted. Apoptosis was measured with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and the expression of cleaved caspase 3 and Bax/Bcl-2. Autophagy was assessed by the expression of light chain protein 3 (LC3) and autophagosomes under transmission electron microscopy. TNFα significantly decreased the number of released oocytes, and many unruptured follicles were observed. TUNEL analysis revealed a larger number of apoptotic cells, and the cleaved caspase 3 and Bax/Bcl-2 increased more than that of the control 12 h after hCG administration. Furthermore, the expression of LC3 wwas significantly higher than that of the control, and autophagosomes were observed in the cytoplasm. Our data indicated that TNFα is an important mediator of ovulation in terms of decreasing the number of released oocytes and inducing granulosa cell death of unruptured follicles via apoptosis and autophagy for remodeling ovarian tissues.////////////////// Effects of tumor necrosis factor-alpha on porcine oocyte meiosis progression, spindle organization, and chromosome alignment. Ma CH et al. OBJECTIVE: To evaluate the effects of tumor necrosis factor-alpha (TNF-alpha) on porcine oocyte maturation, spindle dynamics, and chromosome alignment. DESIGN: Controlled, prospective study. SETTING: University hospital and IVF research laboratory. ANIMAL(S): Ovaries collected from slaughtered prepubertal gilts. MAIN OUTCOME MEASURE(S): Oocyte maturation rate and cytoskeleton distribution. MATERIALS AND METHOD(S): Immature porcine oocytes (GV) were exposed to TNF-alpha at a concentration of 0 (as a control), 1, 5, 10, 100, 200, or 600 ng/mL in M199 medium. Oocytes were cultured for 24 hours to the pre-MI stage or 44 hours to the MII stage. After in vitro maturation for 44 hours, the rates of GV oocytes reaching MII stage were assessed, and MII oocytes were fixed for further examination of the cytoskeleton and the chromosomal distribution. RESULT(S): The TNF-alpha concentration at 5 ng/mL decreased the porcine oocyte maturation rate compared with the control after culture for 44 hours, whereas exposure to 10 or 100 ng/mL TNF-alpha resulted in a significant increase in the frequency of defective spindles or abnormal microfilament distribution. Exposed to 200 ng/mL, TNF-alpha caused a significantly higher abnormality rate of chromosome alignment when compared with the controls. CONCLUSION(S): Exposure of porcine oocytes to an elevated TNF-alpha concentration clearly caused a reduction in their maturation from GV stage to MII stage and increased the proportion of oocytes with abnormal chromosome alignment and cytoskeleton structure. Basini G,et al. reported that hTNF-alpha, it inhibits P4 production in cells from both types of follicles and stimulates E2 output in those from small follicles. it does not affect proliferation, but it stimulates granulosa cell apoptosis. Finally, the effects of hTNF-alpha on bovine granulosa cells are not mediated by nitric oxide or cAMP, as neither of these substances were affected by treatment with the cytokine; however, in some way, they could be mediated through PGE2 and PGF2alpha, the production of which was inhibited by TNF-alpha in cells from small follicles. Tumor necrosis factor alpha (TNF) increases granulosa cell proliferation: dependence on c-Jun and TNF receptor type 1 Son DS, et al . TNF alpha has significant in vitro effects on steroidogenesis and folliculogenesis and reproductive alterations occur in TNF receptor type 1 (TNFR1) knockout mice. The present study investigated the effect of in vitro TNF on granulosa cell proliferation from immature mice at 28 d of age, with emphasis on intracellular signaling that regulates granulosa cell proliferation. TNF dose dependently increased granulosa cell proliferation and the proto-oncogene c-Jun protein. However, other Jun family members such as JunD was expressed constitutively and JunB was not expressed. In vitro TNF did not increase c-Jun and proliferation in granulosa cells from TNFR1 knockout mice. The time course of TNF-induced c-Jun revealed biphasic patterns of short-term (3 h) and long-term (24 h) induction. The time courses of Ser63- and Ser73-phospho c-Jun coincided with changes in total c-Jun. Among MAPK cascades, stress-activated protein kinase/c-Jun-NH(2)-teminal kinase signaling was increased transiently in TNF-treated cells, whereas p38MAPK and ERK1 and 2 were not changed. In addition, overexpression of nuclear factor-kappa B and addition of ceramide and 8-bromo-cAMP did not increase c-Jun or proliferation. Antisense oligonucleotides for c-Jun blocked cell proliferation induced by TNF. In conclusion, the above results demonstrate that TNF increased c-Jun by activating stress-activated protein kinase/c-Jun-NH(2)-teminal kinase signaling via TNFR1 in mouse granulosa cells, and the induced c-Jun resulted in increased cell proliferation. Tumor Necrosis Factor-alpha Induces Apoptosis In Cultured Porcine Luteal Cells Okano A, et al . Some studies in mammalian species recently demonstrated that tumor necrosis factor (TNF-alpha plays an important role for corpus luteum (CL) function by way of apoptosis during the estrous cycle. The objectives of this study were to clarify the induction of apoptosis in cultured porcine luteal cells by TNF-alpha treatment. Luteal cells prepared from porcine ovaries collected from crossbred mature gilts on Days 10-14 of the estrous cycle were isolated and examined as follows: 1) Flow cytometric analysis was carried out to determine apoptosis in cultured luteal cells. 2) Single-cell gel electrophoresis (comet assay) was performed to investigate apoptotic DNA fragmentation in luteal cells. The results of the flow cytometric analysis and comet assay demonstrated coincidentally that TNF-alpha induces DNA fragmentation in luteal cells causing apoptosis. These results revealed that TNF-alpha is an inducing factor of apoptosis in luteal cells. Influence of tumor necrosis factor-alpha on estradiol, progesterone, insulin-like growth factor-II, and insulin-like growth factor binding protein-1, 2, and 3 in cultured human luteinized granulosa cells. Chae H et al. OBJECTIVE: The objective was to investigate the influence of tumor necrosis factor (TNF)-alpha on estradiol, progesterone, insulin-like growth factor (IGF)-II, and insulin-like growth factor binding protein (IGFBP)-1, 2, and 3 in cultured human luteinized granulosa cells. STUDY DESIGN: Human luteinized granulosa cells were obtained from follicular fluid by transvaginal oocyte aspiration from infertile patients undergoing controlled ovarian hyperstimulation (COH) for in vitro fertilization (IVF). The cells were cultured for 72h with TNF-alpha at concentrations of 1.0, 10.0, and 100.0ng/ml. The cells not treated with TNF-alpha served as controls. Radioimmunoassay (RIA) and reverse transcription-polymerase chain reaction (RT-PCR) were used to examine the influence of TNF-alpha on estradiol, progesterone, IGF-II, and IGFBP-1, 2, and 3. Results were analyzed using the Kolmogorov-Smirnov test and analysis of variance (ANOVA). Statistical significance was defined as p<0.05. RESULTS: The concentrations of progesterone seemed to decrease as the concentrations of TNF-alpha increased and the concentration of progesterone in the 100.0ng/ml TNF-alpha group was significantly lower than that in the control and other TNF-alpha groups. The expressions of IGF-II mRNA in the 10.0 and 100.0ng/ml TNF-alpha groups were significantly lower than that in the control group. The expressions of IGFBP-2 mRNA seemed to be decreased in the 10.0 and 100.0ng/ml TNF-alpha groups compared with that in the control group, but there were no statistical significances. CONCLUSION: TNF-alpha may play a role as a regulator of human ovarian physiology by modulating the IGF systems in luteinized granulosa cells. Interactions between progesterone and tumor necrosis factor-{alpha} in the regulation of primordial follicle assembly. Nilsson EE et al. Follicle assembly is the process by which groups or 'nests' of oocytes break down to form primordial follicles. The size of the primordial follicle pool is the major determinant of the reproductive lifespan of a female. Previously, progesterone (P(4)) has been shown to inhibit follicle assembly, while tumor necrosis factor-alpha (TNFalpha) has been shown to promote the apoptosis that is necessary for follicle assembly. The present study examines how TNFalpha and progesterone interact to regulate primordial follicle assembly. Ovaries were collected from newborn rats and placed in organ culture to examine the actions of P(4) and TNFalpha. P(4) was found to decrease primordial follicle assembly and increase the percentage of unassembled oocytes both in vitro and in vivo. TNFalpha treatment did not change the proportion of assembled follicles in cultured ovaries, but blocked the ability of P(4) to inhibit follicle assembly. Microarray analysis of the ovarian transcriptome revealed that progesterone treatment of the ovaries altered the expression of 513 genes with 132 only expressed after P(4) treatment and 16 only expressed in control ovaries. The majority of genes were up-regulated greater than twofold over control, with a small subset of 16 genes down-regulated. Categories of genes affected by P(4) are described including a group of extracellular signaling factors. The progesterone receptors expressed at the time of follicle assembly included the surface membrane progesterone receptors PGRMC1, PGRMC2, and RDA288. The nuclear genomic P(4) receptor was not expressed at appreciable levels. Progesterone increased the expression of several genes (TANK, NFkappaB, Bcl2l1, and Bcl2l2) involved in a signaling pathway that promotes cell survival and inhibits apoptosis. Observations indicate that P(4) acts through the surface membrane progesterone receptors to regulate primordial follicle assembly, and that TNFalpha can override the inhibitory actions of P(4) on follicle assembly. A major mechanism involved in the actions of P(4) is an increase in cell survival genes and inhibition of the apoptosis pathway. Observations provide insight into the hormonal regulation of primordial follicle assembly and lead to novel approaches to potentially manipulate follicle assembly and reproductive capacity. Infusion of Exogenous Tumor Necrosis Factor Dose Dependently Alters the Length of the Luteal Phase in Cattle: Differential Responses to Treatment with Indomethacin and L-NAME, a Nitric Oxide Synthase Inhibitor. Skarzynski DJ et al. We examined whether prostaglandins (PGs) and nitric oxide (NO) mediate tumor necrosis factor (TNF) actions in the estrous cycle. On Day 14 of the cycle, the following solutions were infused into the aorta abdominalis of a total of 51 heifers (Exp.1 and 2): saline, 1 or 10 microg of TNF, an inhibitor of prostaglandin H synthase (INDOmethacin; 480 mg), an inhibitor of NO synthase (L-NAME; 800 mg) or TNF (1 or 10 microg) in combination with INDO or L-NAME. One microg of TNF infused directly into aorta abdominalis increased the PGF2alpha and decreased progesterone (P4) concentration in the peripheral blood and shortened of the cycle. The high TNF dose stimulated P4 and PGE2, and prolonged the CL lifespan. INDO blocked the effects of both TNF doses on the CL lifespan and hormone output. L-NAME completely blocked the effects of the luteolytic TNF dose, whereas the effects of the luteotropic TNF dose were not inhibited. In Exp. 3 (Day 14), saline or different TNF doses were infused into the jugular vein (n=9) or into the uterine lumen (n=18). The CL lifespans of the different groups were not different when TNF was infused into the jugular vein. Although high TNF doses (1, 10 microg) infused into the uterine lumen prolonged the CL lifespan, low doses (0.01, 0.1 microg) induced premature luteolysis. We suggest that the actions of exogenous TNF on the CL lifespan depend on PG synthesis stimulated by TNF in the uterus. TNF at low concentrations initiates a positive cascade between uterine PGF2alpha and various luteolytic factors including NO to complete premature luteolysis. PGE2 is a good candidate as a mediator of the luteotropic actions of exogenous TNF action. Tumor necrosis factor-alpha activates nuclear factor-kappaB but does not regulate progesterone production in cultured human granulosa luteal cells. Gonzalez-Navarrete F et al. Background. The role of tumor necrosis factor-alpha (TNF-alpha) in granulosa luteal cell function and steroidogenesis is still controversial. Our aim was to examine the steroidogenic response, together with the simultaneous expression and activation of nuclear factor-kappaB (NF-kappaB), in cultured human granulosa luteal cells (GLCs) following administration of TNF-alpha. Materials and methods. This prospective controlled study was conducted in the Human Reproduction Division at the Institute of Maternal and Child Research, Faculty of Medicine, University of Chile and the San Borja Arriar?Hospital, National Health Service, Santiago, Chile. GLCs were obtained from aspirates of follicles from women undergoing in vitro fertilization (IVF). Thirty-two women undergoing IVF for tubal-factor and/or male-factor infertility participated in this study. Protein levels of NF-kappaB, the NF-kappaB inhibitor IkappaBalpha and steroidogenic acute regulatory protein (StAR) were determined by Western blot and localization of NF-kappaB was studied by indirect immunofluorescence. Progesterone production was determined by radioimmunoassay. Results. TNF-alpha did not affect the expression of StAR protein or the synthesis of progesterone. NF-kappaB was expressed in the GLCs and activated by TNF-alpha, resulting in degradation of IkappaBalpha and mobilization of the p65 NF-kappaB subunit into the nucleus. Conclusions. These results indicate that TNF-alpha did not modulate steroidogenesis in cultured human GLCs. However, NF-kappaB was activated by TNF-alpha. Therefore the activation of NF-kappaB via the TNF-alpha pathway is likely associated with other preovulatory granulosa cell processes important for human ovarian function. | ||||
| Expression regulated by | LH | ||||
| Comment | Luteinizing hormone induces ovulation via tumor necrosis factor α-dependent increases in prostaglandin F2α in a nonmammalian vertebrate. Crespo D et al. (2015) Ovulation is induced by the preovulatory surge of luteinizing hormone (LH) that acts on the ovary and triggers the rupture of the preovulatory ovarian follicle by stimulating proteolysis and apoptosis in the follicle wall, causing the release of the mature oocyte. The pro-inflammatory cytokine tumor necrosis factor α (TNFα) and prostaglandin (PG) F2α (PGF2α) are involved in the control of ovulation but their role mediating the pro-ovulatory actions of LH is not well established. Here we show that Lh induces PGF2α synthesis through its stimulation of Tnfα production in trout, a primitive teleost fish. Recombinant trout Tnfα (rTnfα) and PGF2α recapitulate the stimulatory in vitro effects of salmon Lh (sLh) on contraction, proteolysis and loss of cell viability in the preovulatory follicle wall and, finally, ovulation. Furthermore, all pro-ovulatory actions of sLh are blocked by inhibition of Tnfα secretion or PG synthesis and all actions of rTnfα are blocked by PG synthesis inhibitors. Therefore, we provide evidence that the Tnfα-dependent increase in PGF2α production is necessary for the pro-ovulatory actions of Lh. The results from this study shed light onto the mechanisms underlying the pro-ovulatory actions of LH in vertebrates and may prove important in clinical assessments of female infertility.////////////////// | ||||
| Ovarian localization | Oocyte, Granulosa, Theca, Luteal cells, Small luteal cells, Large luteal cells, Follicular Fluid | ||||
| Comment | Prognostic role of follicular fluid tumor necrosis factor alpha in the risk of early ovarian hyperstimulation syndrome. Alhilali MJ et al. (2020) Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic condition characterized by capillary hyperpermeability which can be predicted by preovulatory ovarian responses such as number of follicles. A variety of cytokines are thought to be involved in pathophysiology of this syndrome. A prospective cohort study invloving sixty intracytoplasmic sperm injection (ICSI) patients. On the day of hCG injection, we explored the threshold of larger follicles ≥11 mm diameter with a count of ≥18 follicles for the high-risk moderate-to-severe OHSS and 13-18 follicles for the low-risk moderate-to-severe OHSS. Whereas larger follicles count of less than 13 were classified as normoresponders. Pooled follicular fluid (FF) samples of each patient were collected on the day of oocyte retrieval. Magnetic multiplex immunoassay was explored to measure the concentrations of some intrafollicular cytokines including: GM-CSF, INF-γ, TNF-α, IL-10, CXCL8/IL-8, IL-6, IL-5, IL-4, IL-2, and IL-1β. All sixty patients underwent controlled ovarian hyperstimulation (COH) with either GnRH agonist or antagonist protocols. Intrafollicular TNF-α concentration was significantly different (p < 0.05) in the high-risk moderate-to-severe OHSS patients compared to low-risk moderate-to-severe OHSS patients and normoresponders. TNF-α in FF had a negative correlation with the chance of high-risk moderate-to-severe OHSS. The differences in the risk of OHSS between patients who received GnRH agonist or antagonist were not significant (p > 0.05). In accordance to the negative correlation of TNF-α and high risk of early OHSS, we did not expect TNF-α to play a role in increasing vascular permeability in ovarian tissues. In addition, the risk of early moderate-to-severe OHSS was not affected by different GnRH superovulation protocols.////////////////// Evaluation of cytokines in follicular fluid and their effect on fertilization and pregnancy outcome. Gaafar TM 2014 et al. Cytokines in follicular fluid (FF) are important for reproduction as they modulate oocyte maturation and ovulation which influence subsequent fertilization, development of early embryo and potential for implantation. We evaluated FF cytokines in women who underwent intracytoplasmic sperm injection (ICSI) and their association with fertilized oocytes, embryo quality and pregnancy outcome. FF belonging to 38 patients including 18 polycystic ovary (PCO) and 20 male/unexplained infertility patients were investigated for granulocyte colony stimulating factor (G-CSF), regulated upon activation normal T cell expressed and presumably secreted (RANTES), tumour necrosis factor (TNFa), interferon gamma (IFN?) and interleukins (IL-4 and IL-2) by bead-based sandwich immunoassay. Our findings revealed that on the day of oocyte retrieval, G-CSF was positively correlated with the number of fertilized oocytes, while TNFa detection was associated with reduced number of fertilized oocytes. Only G-CSF showed significant positive effect to the pregnancy outcome although the cytokines studied were not associated with embryo quality. PCO as the cause of infertility did not show an association with cytokines in FF. The functions of cytokines in reproduction are likely to be complex, and cytokine evaluation may offer insight to the understanding of the mechanisms leading to success or failure of assisted reproduction. ///////////////////////// Roby KF, et al.firstly reported that immunoreactive TNF alpha (I-TNF) was observed in granulosa cells of healthy antral and atretic follicles and appeared to be secreted by the granulosa cells, since it was present in the follicular fluid surrounding antral and degenerating granulosa. Marcinkiewicz JL, et al. later reported that TNF alpha also localizes to all oocytes in the adult, including ovulated oocytes within the oviduct.Kondo H,et al. found that TNF alpha immunostaining was also present within the oocyte in primordial follicles of the adult ovary. Positive immunostaining for TNF alpha in granulosa cells became apparent in preantral follicles, while that in theca interna cells began to appear at the antral follicle stage. The staining intensity of the oocyte increased as the oocyte reached the preovulatory stage. The intensity of immunostaining for TNF alpha in the granulosa and thecal cells increased as the follicle became larger and matured. In corpora lutea, the immunostaining for TNF alpha persisted in the granulosa lutein and theca lutein cells and intensified in the mid luteal phase. In the regressing corpora lutea, TNF alpha immunostaining in the luteal cells decreased as the regression advanced. Expression of TNF-alpha mRNA, but not of TNF-alpha receptors mRNA, is detected in single murine oocyte and decreases during oocyte meiotic maturation: single-cell RT-PCR data. Shepel OA et al. The present study was conducted to investigate the expression of TNF-alpha and its receptors (types I and II) in both oocytes with germinal vesicle and the first polar body in mice. | ||||
| Follicle stages | Primordial, Primary, Secondary, Antral, Preovulatory, Corpus luteum | ||||
| Comment | TNF{alpha} ACTIVATES ICER TRANSCRIPTION AND REPRESSES P450AROM AND INHIBIN {alpha}-SUBUNIT EXPRESSION IN RAT OVARIAN GRANULOSA CELLS BY A p44/42 MAPK-DEPENDENT MECHANISM. Morales V et al. The proinflammatory cytokine TNFalpha has important actions at the level of the ovary, among others inhibition of P450AROM aromatase activity and the secretion of inhibin, two proteins that are markers of the granulosa cells differentiated status. Because the transcription of both P450AROM and inhibin alpha-subunit can be suppressed in the ovary by ICER, the inducible repressor isoform of CREM, we have investigated if TNFalpha and its intracellular messenger ceramide can induce ICER expression and the mechanisms whereby the induction is accomplished. ICER mRNA levels were assessed by RT-PCR in granulosa cells treated with TNFalpha, the ceramide mobilizing enzyme sphingomyelinase or C6-cer a cell permeant ceramide analog. Rapid (3 h) yet transient increases in the four isoforms of ICER were observed en response to all treatments. Likewise ICER protein measured by immunoprecipitation with a specific Ab increases after TNFalpha, SMase or C6-cer treatment. The mandatory phosphorylation of CREB was also observed in response to TNFalpha, SMase or C6-cer and shown to be prevented by the p44/42 MAPK specific inhibitor PD098059 but no other kinases blockers. Activation of p44/42 MAPK by the cytokine and its messenger was subsequently demonstrated as well as the inhibition of ICER expression by PD098059. Finally the blocking of p44/42 MAPK activation prevented TNFalpha inhibition of FSH-dependent increases in P450AROM and inhibin alpha-subunit mRNA levels, thus indicating that p44/42 MAPK-mediated ICER expression may be accountable for the effects of TNFalpha on the expression of both proteins. | ||||
| Phenotypes |
PCO (polycystic ovarian syndrome) |
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| Mutations |
7 mutations
Species: mouse
Species: human
Species: human
Species: human
Species: human
Species: human
Species: human
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
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| last update: | Nov. 24, 2020, 11:55 p.m. | by: | hsueh email: |
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