Okamura et al. (1995) cloned an interferon-gamma-inducing factor that augments natural killer (NK) cell activity in spleen cells. The gene encodes a precursor protein of 192 amino acids and a mature protein of 157 amino acids, which had no obvious similarities to any known peptide. Messenger RNAs for the gene, designated IGIF by them.//////Involved in pyroptosis
NCBI Summary:
The protein encoded by this gene is a proinflammatory cytokine of the IL-1 family that is constitutively found as a precursor within the cytoplasm of a variety of cells including macrophages and keratinocytes. The inactive IL-18 precursor is processed to its active form by caspase-1, and is capable of stimulating interferon gamma production, and of regulating both T helper (Th) 1 and Th2 responses. This cytokine has been implicated in the injury of different organs, and in potentially fatal conditions characterized by a cytokine storm. In humans, IL-18 gene is located on chromosome 11. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Aug 2020]
Expression of interleukin-18 and its receptor in mouse ovary. Tsuji Y et al. (2002) Interleukin-18 (IL-18) strongly induces interferon-gamma production and is produced not only by types of immune cells but also by types of non-immune cells. Ovulation is thought to be an inflammation-like reaction in which many pro-inflammatory cytokines are involved. We investigated whether IL-18 is involved in the functions of ovary. The 4-week-old immature female mice were examined for IL-18 and IL-18 receptor (IL-18R) expression on their ovaries under stimulation with pregnant mare's serum gonadotropin (PMSG) and human chorionic gonadotropin (hCG) by immunohistochemical staining, Western blotting and reverse transcript-polymerase chain reaction. The IL-18R was blocked by the injection of anti-IL-18R monoclonal antibody to immature mice during PMSG-hCG stimulation, and the number of ovulated ova was counted. The expression of both proteins and mRNA of IL-18 and IL-18R were very low in immature ovaries before stimulation, but after PMSG injection both IL-18 and IL-18R increased dramatically in theca cells and reached a maximum level at the peri-ovulatory phase then slightly lowered, but still kept a high level during the luteal phase in the corpus luteum. The treatment of IL-18R monoclonal antibody to the mice during ovarian stimulation reduced the number of ovulated ova and inhibited the expansion of cumulus cells surrounding the ovum. IL-18 and IL-18R play roles in various kinds of function of ovary.//////////////////Interleukin-18 is High in the Serum of IVF Pregnancies with Ovarian Hyperstimulation Syndrome Gutman G, et al 2004 .
The presence of interleukin-18 (IL-18) in serum and pre-ovulatory follicular fluid (FF) and its possible correlation to in-vitro fertilization/embryo transfer (IVF/ET) outcome and ovarian hyperstimulation syndrome (OHSS) development. Method of study: A prospective study was carried out. Assays for serum and pooled pre-ovulatory FF levels of IL-18 were performed on 30 patients who underwent oocyte retrieval for IVF/ET. Results: Mean serum and FF levels of IL-18 were 370.4 +/- 224 and 228.9 +/- 208 pg/mL, respectively (r = 0.77, P < 0.0001). Levels of FF IL-18 were comparable between the two ovaries (right = 221 +/- 166.8 pg/mL, left = 237 +/- 171.9 pg/mL; r = 0.7550, P = 0.49). A positive correlation was found between IL-18 FF levels and number of retrieved oocytes (r = 0.45; P = 0.019). In three patients (10%) who developed OHSS, the mean serum level of IL-18 at day of ovum pickup was significantly higher compared with patients without OHSS (620 +/- 196 pg/mL versus 345 +/- 251 pg/mL, respectively, P = 0.04). Conclusions: Both pre-ovulatory FF and serum levels of IL-18 correlate with the number of retrieved oocytes. The serum IL-18 level at day of ovum pickup may predict consequent development of OHSS. Further investigations are warranted to determine the role of IL-18 in the folliculogenesis and OHSS pathogenesis.
Expression regulated by
FSH, LH
Comment
Ovarian localization
Granulosa, Theca, Luteal cells, Follicular Fluid
Comment
IL-18 and IL-18 binding protein concentration in ovarian follicular fluid of women with unexplained infertility to PCOS during in vitro fertilization. Zhang H et al. (2020) The correlation between the concentration of interleukin (IL) 18 in follicular fluid and the pathogenesis of Polycystic Ovary Syndrome (PCOS) is unclear. Therefore, we tested the IL-18 and IL-18 binding protein (IL-18BP) levels in follicular fluid (FF) and serum in PCOS women undergoing reproductive measures and to explore their possibly correlation with PCOS. Serum and pooled follicular fluid levels of IL-18, IL-18BP and IL-18/IL-18BP ratios were evaluated in sixty patients with PCOS and sixty women with unexplained infertility undergoing in vitro fertilization. The FF IL-18 levels were increased in PCOS group than the CON group (p < 0.01), and the IL-18 levels were significantly higher in the FF than in serum in PCOS group. Furthermore, the elevated FF IL-18 levels have no correlation with the serum IL-18 levels. Additionally, the expression of IL-18 in the follicular fluid of the overweight PCOS patients was increased compared to the normal weight PCOS patients, while in the overweight patients, FF IL-18 was significantly higher in the PCOS group than in the control group. The FF IL-18 and IL-18BP may have a local involvement in the pathogenesis of PCOS. The PCOS itself and overweight will aggravate the local inflammatory response in the ovary. Further studies are needed to elucidate this issue.//////////////////
Expression of mRNA and protein of IL-18 and its receptor in human follicular granulosa cells. Salmassi A et al. (2016) There is no information available about the IL-18 receptor in ovarian follicles, so the present study attempts to demonstrate the expression of IL-18 and its receptor in human granulosa cells (GCs). To evaluate the concentration of IL-18 in serum and follicular fluid (FF), we collected serum and FF from 102 women undergoing oocyte retrieval. Also, to detect expression of IL-18 and its receptor by luteinized GCs, these cells were pooled six times from a total of twenty individual patients with 5-16 follicles each. The IL-18 concentration was determined by ELISA and the expression of IL-18 and its receptor by immunocytochemistry and reverse transcription polymerase chain reaction. Our results showed that the median IL-18 concentration in serum, 159.27 pg/ml (IQR 121.41-210.1), was significantly higher than in FF, 142.1 pg/ml (IQR 95.7-176.5), p < 0.001. Moreover, we found that IL-18 and its receptor are expressed by GCs. The presence of IL-18 in FF and the expression of IL-18 and its receptor by GCs suggest an important role for this cytokine in ovarian function.//////////////////
Expression of CD11c+HLA-DR+dendritic cells and related cytokines in the follicular fluid might be related to pathogenesis of ovarian hyperstimulation syndrome. Shi SL et al. (2016) To explore the expressions of CD11c+HLA-DR+dentritic cells in the follicular fluid of patients with OHSS and their significances. 100 individuals. embryos were observed. The distribution of dentritic cells in follicular fluid and the levels of IL-10, IL-12, IL-18 and IL-23 in follicular fluid were detected. There were ovarian hyperstimulation syndrome (OHSS) group and control group in this study. The OHSS group consisted of 50 patients with OHSS and the control group consisted of 50 patients who underwent in vitro fertilization-embryo transfer (IVF-ET) only due to male factors. The statuses of embryos were compared between the two groups. The distribution of dentritic cells in follicular fluid was determined with flow cytometry, and the levels of IL-10, IL-12, IL-18 and IL-23 in follicular fluid were detected with enzyme-linked immunosorbent assay (ELISA) in all patients. The two-pronuclear (2PN) fertility rate, high-quality embryo rate and available embryo rate were all significantly lower in OHSS group than in control group (all P<0.05). The number of CD11c+HLA-DR+dentritic cells (P<0.05) and the levels of IL-10, IL-12, IL-18 and IL-23 were all significantly higher in OHSS group than in control group (all P<0.01). The follicular fluid of the patients with OHSS is in an inflammatory status, the inflammatory status may be involved in OHSS and the microenvironment of follicular fluid may affects oocyte quality and embryo development.//////////////////IL-18 and IL-18 binding protein concentrationin ovarian follicular fluid of women with 'tubalfactor' subjected to in vitro fertilization. Radwan P et al. Introduction: Composition of follicular fluid is also regarded to be linked to quality of oocytes, fertilizationand quality of the embryo. The aim of this study was to investigate the concentration of IL-18and IL18BP in follicular fluid (FF) in a homogeneous group of women with sterility caused by'tubal factor' subjected to in vitro fertilization (IVF) and the relation between concentrate ofthis cytokine and IVF outcome. Matherials/Methods: The study group consisted of 83 non-smoking women aged 30.9 3.2 (23.0-43.0) with confirmed(hysterosalpingography and/or laparoscopy) bilateral complete tubal impermeability. Follicularfluid levels of IL-18 and IL18BP were evaluated in 83 patients undergoing in vitro fertilization(IVF). Ovarian hormonal stimulation was conducted according to a GnRH antagonist protocol.The measurement of IL-18 and IL18BP in follicular fluid was done using the ELISA method. Results: The mean follicular levels of IL-18 and IL18BP were 468.5 357.4 pg/ml and 8611.3 534 pg/ml. The biochemical pregnancy rate was 39.7% (33/83); 22 women became clinically pregnant(26.5%). The implantation rate was 26.7% (36/135). No significant correlation was found betweenfollicular concentrations of IL-18 and age of the patients (r=0.13 p>0.05), number ofmetaphase II oocytes collected (r=-0.11 p>0.05), number of 3-day embryos (r=-0.157 p>0.05),biochemical pregnancies (r=0.03 p>0.05), or clinical pregnancies (r=-0.06 p>0.05). Also therewas no significant correlation between IL18BP and age of the patients (r=0.21 p>0.05), numberof metaphase II oocytes collected (r=0.08 p>0.05), number of 3-day embryos (r=-0.19 p>0.05),biochemical pregnancies (r=0.11 p>0.05) and clinical pregnancies (r=-0.34 p>0.05). Conclusion: IL-18 and IL18BP are detectable in follicular fluid but do not determine IVF outcome in womenwith 'tubal factor'. IL-18 and IL18BP are not promising prognostic markers for IVF successin this subgroup of patients.
Tsuji Y, et al reported the expression of interleukin-18 and its receptor in mouse ovary.
Interleukin-18 (IL-18) strongly induces interferon-gamma production
and is produced not only by types of immune cells but also by types of
non-immune cells. Ovulation is thought to be an inflammation-like reaction in
which many pro-inflammatory cytokines are involved.
4-week-old immature female mice were examined for IL-18 and IL-18 receptor
(IL-18R) expression on their ovaries under stimulation with pregnant mare's
serum gonadotropin (PMSG) and human chorionic gonadotropin (hCG) by
immunohistochemical staining, Western blotting and reverse
transcript-polymerase chain reaction indicated the
expression of both proteins and mRNA of IL-18 and IL-18R were very low in
immature ovaries before stimulation, but after PMSG injection both IL-18 and
IL-18R increased dramatically in theca cells and reached a maximum level at the
peri-ovulatory phase then slightly lowered, but still kept a high level during the
luteal phase in the corpus luteum. The treatment of IL-18R monoclonal antibody
to the mice during ovarian stimulation reduced the number of ovulated ova and
inhibited the expansion of cumulus cells surrounding the ovum.
Ovarian follicular concentration of IL-12, IL-15, IL-18 and p40 subunit of IL-12 and IL-23. Vujisic S et al. BACKGROUND: The aim of the study was to determine the presence of interleukin (IL)-12, IL-15, IL-18 and p40 subunit of IL-12/IL-23 in follicular fluid from spontaneous cycles and the relation between the concentration of selected cytokines and IVF-embryo transfer outcome. METHODS: IVF-embryo transfer and enzyme immunoassay (EIA) (R&D Systems, Minneapolis, MN, USA and MBL, Nagoya, Japan) were used. RESULTS: Follicular fluid of women included in the IVF-embryo transfer procedure contained common p40 subunit of IL-12/IL-23 (median 70.1 pg/ml), IL-15 (median 1.3 pg/ml) and IL-18 (median 38.2 pg/ml). There was a significant negative correlation between follicular fluid concentrations of IL-15 and IL-18 (R = -0.392, P = 0.003). Significantly higher concentrations of common p40 subunit of IL-12/IL-23 (median 79.8 pg/ml) were found in the follicular fluid taken from follicles containing oocytes, when compared with those without an oocyte (median 44.5 pg/ml, P = 0.006). Patients who achieved clinical pregnancy had significantly decreased concentration of IL-15 (median 0.8 pg/ml) compared with patients without successful IVF-embryo transfer outcome (median 1.4 pg/ml, P = 0.047). CONCLUSION: Follicular fluid collected from spontaneous cycles contains detectable levels of p40 subunit of IL-12/IL-23, IL-15 and IL-18. Increased concentrations of p40 subunit of IL-12/IL-23 in follicles containing oocytes suggest an important role of this cytokine in reproduction. Possible negative value of IL-15 as a predictor of IVF-embryo transfer success remains to be determined.
Follicle stages
Comment
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
3 mutations
Species: human
Mutation name: None
type: naturally occurring fertility: subfertile Comment: Association of polymorphisms of interleukin-18 gene promoter region with polycystic ovary syndrome in Chinese population. Yang Y et al. ABSTRACT: BACKGROUND: Recent research shows that polycystic ovary syndrome (PCOS) may have an association with low-grade chronic inflammation, and that PCOS may induce an increase in serum interleukin-18 (IL-18) levels. METHODS: To investigate the polymorphisms of the IL-18 gene promoters with PCOS, two single nucleotide polymorphisms (SNPs) in the promoter of the IL-18 gene (at positions -607C/A and -137G/C) in 118 Chinese women with PCOS and 79 controls were evaluated using polymerase chain reaction (PCR). RESULTS: No significant differences were found in the genotype distribution, allele frequency and haplotype frequency between the PCOS and control groups. Further analysis demonstrated a relationship between IL-18 gene promoter polymorphisms and PCOS insulin resistance (IR). Regarding the -137 allele frequency, G and C allele frequencies were 93.5% and 6.5%, respectively, in the PCOS with IR patients; G and C allele frequencies were 85.4% and 14.6%, respectively, in PCOS patients without IR (chi2=3.601, P=0.048). CONCLUSIONS: The presence of a polymorphism in the IL-18 gene was found to have no correlation with the occurrence of PCOS. Carriage of the C allele at position -137 in the promoter of the IL-18 gene may play a protective role from the development of PCOS IR.
Is interleukin-18 associated with polycystic ovary syndrome? Yang Y et al. ABSTRACT: BACKGROUND: Recent research show that polycystic ovary syndrome (PCOS) may have an association with low-grade chronic inflammation, IL-18 is considered as a strong risk marker of inflammation. METHODS: To investigate serum IL-18 concentrations in PCOS patients and focus on its relationship between obesity and insulin resistance (IR). Sixty consecutive women with PCOS and thirty controls were recruited. Serum level of IL-18 and fasting blood glucose, fasting insulin, follicle-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone (T) were measured. RESULTS: Serum levels of IL-18 was significantly higher in the PCOS group than in the control group. Serum level of IL-18 was higher in the PCOS group with IR than in the PCOS group without IR. Serum level of IL-18 was higher in obese PCOS patients than in lean PCOS patients. Serum level of IL-18 was higher in lean PCOS patients than in the lean control group. Serum level of IL-18 in the PCOS group was positively related to BMI, IR index and T. CONCLUSION: IL-18 level was increased in PCOS patients, and correlated with insulin resistance, obesity and hyperandrogenism.
Species: human
Mutation name: None
type: naturally occurring fertility: subfertile Comment: Association of IL-18 genotype with impaired glucose regulation in Korean women with polycystic ovary syndrome. Kim JW et al. OBJECTIVE: Polycystic ovary syndrome (PCOS) is a common endocrine disorder among women of reproductive age. The pro-inflammatory cytokine, interleukin (IL)-18, is associated with metabolic syndrome, and elevated serum IL-18 levels are related to obesity and insulin resistance in PCOS patients. However, the role of IL-18 in the PCOS remains unclear. So we examined whether or not two functional polymorphisms in the IL-18 gene, -137G>C and +183A>G, are associated with PCOS itself or glucose intolerance in Korean women with PCOS. STUDY DESIGN: The IL-18 genotypes of 126 women with PCOS and 113 controls were determined and their serum levels of lipid and hormone profiles measured. The insulin resistance index was calculated from the glucose and insulin concentrations obtained by oral glucose tolerance tests. RESULTS: There were no statistically significant differences in the distribution of -137 G>C polymorphisms among the women classified according to presence or absence of PCOS and obesity. However, the -137G/G allele was more frequent in the PCOS+impaired glucose regulation (IGR) group than PCOS+normal glucose tolerance group (X(2)=7.637, p(Bonf)=0.022). The PCOS group with only the -137G allele had a significantly increased risk of IGR compared to the PCOS group with the -137C allele (92 vs. 8%, odds ratio=6.325, 95% confidence interval=1.403-28.519). In the PCOS patients, the mean fasting and 2-h post-prandial plasma glucose level of patients with only the -137G allele was significantly higher than those of the patients with the -137C allele (88.87?9.49 vs. 84.37?6.19, p=0.002 and 120.07?34.53 vs. 107.54?27.13, p=0.038). Only one woman was heterozygous for the +183A>G polymorphism and the other 224 subjects were homozygous for the polymorphism (A/A). CONCLUSION: The IL-18 -137G allele could play a role in the predisposition to glucose intolerance in Korean women with PCOS, and the +183G allele of IL-18 is not associated with the Korean population.
Species: mouse
Mutation name: type: null mutation fertility: fertile Comment: Enhanced viral clearance in interleukin-18 gene-deficient mice after pulmonary infection with influenza A virus. Van Der Sluijs KF et al. (2005) T helper 1 driven immune responses facilitate host defence during viral infections. Because interleukin-18 (IL-18) mediates T helper 1 driven immune responses, and since mature IL-18 is up-regulated in human macrophages after influenza virus infection in vitro, it has been suggested that IL-18 plays an important role in the immune response to influenza. To determine the role of IL-18 in respiratory tract infection with influenza, IL-18 gene-deficient (IL-18(-/-)) and normal wildtype mice were intranasally inoculated with influenza A virus. Influenza resulted in an increase in constitutively expressed IL-18 in the lungs of wildtype mice. The clearance of influenza A was inhibited by IL-18, as indicated by reduced viral loads on day 8 and day 12 after infection in IL-18(-/-) mice. This enhanced viral clearance correlated with increased CD4(+) T-cell activation in the lungs as reflected by CD69 expression on the cell surface. Surprisingly, interferon-gamma (IFN-gamma) levels were similar in the lungs of IL-18(-/-) mice and wildtype mice. Intracellular IFN-gamma staining revealed similar expression levels in lung-derived natural killer cells, CD4(+) and CD8(+) T cells, indicating that IFN-gamma production is IL-18-independent during influenza virus infection. Tumour necrosis factor-alpha production by CD4(+) T cells was significantly lower in IL-18(-/-) mice than in wildtype mice. Our data indicate that endogenous IL-18 impairs viral clearance during influenza A infection.//////////////////