Using a human cDNA library that was enriched by subtractive hybridization for sequences expressed by T lymphocytes but not B lymphocytes, Schall et al. (1988) isolated a gene (D17S136E), which they designated RANTES, that encodes a novel T cell-specific molecule. (RANTES is an acronym for 'Regulated upon Activation, Normally T-Expressed, and presumably Secreted.')
RANTES is one of the natural ligands for the chemokine receptor CCR5 and potently suppresses in vitro replication of the R5 strains of HIV-1, which use CCR5 as a coreceptor.
NCBI Summary:
This gene is one of several chemokine genes clustered on the q-arm of chromosome 17. Chemokines form a superfamily of secreted proteins involved in immunoregulatory and inflammatory processes. The superfamily is divided into four subfamilies based on the arrangement of the N-terminal cysteine residues of the mature peptide. This chemokine, a member of the CC subfamily, functions as a chemoattractant for blood monocytes, memory T helper cells and eosinophils. It causes the release of histamine from basophils and activates eosinophils. This cytokine is one of the major HIV-suppressive factors produced by CD8+ cells. It functions as one of the natural ligands for the chemokine receptor chemokine (C-C motif) receptor 5 (CCR5), and it suppresses in vitro replication of the R5 strains of HIV-1, which use CCR5 as a coreceptor. Alternative splicing results in multiple transcript variants that encode different isoforms. [provided by RefSeq, Jul 2013]
General function
Ligand, Cytokine, Cell adhesion molecule
Comment
Previous studies showing that peripheral blood mononuclear cells or CD4+ lymphocytes obtained from different individuals have wide variations in their ability to secrete RANTES prompted Liu et al. (1999) to analyze the upstream noncoding region of the RANTES gene, which contains cis-acting elements involved in RANTES promoter activity, in HIV-1-infected and non-HIV-1-infected individuals in Japan. They found 2 polymorphic positions, 1 of which was associated with reduced CD4+ lymphocyte depletion rates during untreated periods in HIV-1-infected individuals.
CCL5 secreted by senescent theca-interstitial cells inhibits preantral follicular development via granulosa cellular apoptosis. Shen L et al. (2019) As a fundamental aging mechanism, cellular senescence causes chronic inflammation via the senescence-associated secretory phenotype (SASP). Theca-interstitial cells are an essential but little-studied component of follicle development in the ovarian microenvironment. In the present study, we observed significant cellular senescence in theca-interstitial cells and secretion of chemokine (C-C motif) ligand 5 (CCL5) by these cells during aging. Furthermore, we aimed to investigate whether and how senescence-associated secretory phenotype (SASP)-associated CCL5 may be involved in follicle development. Increased levels of CCL5 in the microenvironment of follicles attenuated preantral follicle growth, survival, and estradiol secretion. Oocyte maturation and the expression of zona pellucida 3 and differentiation factor 9 (GDF9) were also inhibited by CCL5. Granulosa cell apoptosis in follicles was promoted by CCL5, accompanied by the phosphorylation of nuclear factor-κB by CCL5 and inhibition of the PI3K/AKT pathway. These results suggest that SASP-associated CCL5 produced by senescent theca-interstitial cells may impair follicle development and maturation during ovarian aging by promoting granulosa cell apoptosis.//////////////////
Aust et al hypothesized that RANTES may he one of the chemoattractants involved in stimulating eosinophils and macrophages to migrate selectively into bovine dominant follicles and into developing corpora lutea, They sequenced a 736 bp fragment of the bovine RANTES mRNA encoding the complete protein and defined the ovarian source of RANTES mRNA, As demonstrated by competitive RT-PCR, follicle-derived macrophages showed a 100-1000 times higher RANTES mRNA level compared to unpurified granulosa cells or follicle-derived fibroblasts.
Genes whose expression is detected by cDNA array hybridization: stress response, cell/cell communication Rozenn Dalbi?Tran and Pascal Mermilloda
Expression regulated by
Growth Factors/ cytokines, TNF
Comment
Pathogen-associated molecular patterns initiate inflammation and perturb the endocrine function of bovine granulosa cells from ovarian dominant follicles via TLR2 and TLR4 pathways. Price JC 2013 et al.
Bacterial infections of the uterus or mammary gland commonly cause disease and infertility by perturbing growth and steroidogenesis of the dominant follicle in the ovary of cattle. Cells of the innate immune system use Toll-like receptors TLR2, TLR4 and TLR5 to recognize pathogen-associated molecular patterns (PAMPs) expressed by bacteria, leading to activation of MAPK and NF?B pathways, and production of inflammatory cytokines such as IL-1?and IL-6, and the chemokine IL-8. The present study tested whether granulosa cells from dominant follicles have functional TLR2, TLR4 and TLR5 pathways. Supernatants of primary bovine granulosa cells accumulated IL-1? IL-6 and IL-8 when treated for 24 h with PAM that binds TLR2 or LPS that binds TLR4, but not flagellin that binds TLR5. Granulosa cell responses to PAM or LPS were rapid, with increased phosphorylation of p38 and ERK1/2 within 30 min and increased abundance of IL6, IL1B, IL10, TNF, IL8 and CCL5 mRNA after 3 h treatment. Accumulation of IL-6 in response to PAM and LPS was attenuated using siRNA targeting TLR2 and TLR4, respectively. Furthermore, treating granulosa cells with inhibitors targeting MAPK or NF?B reduced the accumulation of IL-6 in response to LPS or PAM. Treatment with LPS or PAM reduced the accumulation of estradiol and progesterone, and the PAMPs reduced granulosa cell expression of CYP19A1 mRNA and protein. In conclusion, bacterial PAMPs initiate inflammation and perturb the endocrine function of bovine granulosa cells from dominant follicles via TLR2 and TLR4 pathways.Pr?s: A rapid inflammatory response to pathogen-associated molecular patterns mediated by TLR2 and TLR4 pathways in granulosa cells provides a molecular explanation of how bacterial infections distant to the ovary can perturb dominant follicle function.
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Machelon V et al examined the production of RANTES chemokine, which may contribute to the recruitment and local accumulation of leukocytes in human preovulatory follicles. Cells were
obtained from follicular aspirates collected from in vitro fertilization patients, then cultured. RANTES production in culture was measured by immunoenzymatic assay, RANTES-producing cells were measured by flow cytometry,
and messenger ribonucleic acid as measured by RT-PCR and in situ
hybridization. RANTES was detected in follicular fluids and culture
supernatants; RANTES protein and messenger ribonucleic acid were expressed in
granulosa cells. RANTES production was stimulated by tumor necrosis
factor-alpha (TNF alpha) This
suggests that RANTES may play an active role in ovarian processes involving
the local accumulation of immune cells. Gabriela Aust et al 2000 reported the role of RANTES and eotaxin in eosinophil attraction into periovulatory structures.
They evaluated the presence and number of eosinophils at varying stages in the human corpus luteum from 27 ovaries of women at reproductive age. Eosinophils preferentially accumulated in dilated microvessels of the thecal layer transforming into septa of the corpus luteum. The granulosa layer under luteinization, the thecal layer, and haemorrhages in the former antrum each contained low, moderate and high numbers of extravasated eosinophils respectively. Eosinophils decreased rapidly during the stages of secretion and regression. Semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) systems were used to investigate the expression and regulation of the eosinophil-attracting chemokines RANTES (regulated on activation, normal T cell expressed and secreted) and eotaxin in granulosa cells obtained from follicular aspirates from women undergoing IVF. Contaminating leukocytes were determined by CD18 mRNA quantification. Granulosa cells expressed RANTES (n = 3; 43 ? 14 pg/ml, mean ? SEM). 4?phorbol-12-myristate-13-acetate (PMA; 211 ? 53) and tumour necrosis factor (TNF ) (238 ? 59), but not interleukin (IL)-1 up-regulated RANTES at significant levels. In general, higher basal and stimulated RANTES mRNA and protein were found in cultures with higher CD18 mRNA levels than in those with lower levels.
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.
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By means of in situ hybridization,Aust et al found RANTES mRNA positive macrophages were located in the former thecal layer of the developing corpora lutea.
Follicle stages
Corpus luteum, Follicular fluid
Comment
Karstrom-Encrantz et al investigated the presence in the ovary of RANTES (regulated upon activation, normal T-cell expressed and secreted), which has specific chemotactic activity towards monocytes/T-cells/eosinophils. The concentrations of the cytokine were first measured in follicular fluid and peripheral blood from a group of patients undergoing in-vitro fertilization (IVF) procedures. The concentrations of RANTES in follicular fluid were only 1/50 of those in blood plasma. RANTES protein was not detectable in the culture medium of granulosa-lutein cells neither during basal nor IL-1beta stimulated conditions.
Burke et al defined a cytokine mRNA profile of ovarian cancers, using RT-PCR. The profile, based on screening for 25 cytokines and 12 receptor mRNAs, was rich in growth factors, pro-inflammatory cytokines and chemokines, but weak in lymphocyte-associated cytokines. Chemokines RANTES, MIP-1 alpha and MIP-1 beta were expressed in biopsies, but were rarely detected in cell lines and absent from xenografts.