Leukemia inhibitory factor (LIF) is a pleiotropic cytokine of the interleukin-6 family and has different biological actions in various tissue systems. Although named for its ability to inhibit proliferation of a myeloid leukemic cell line by inducing differentiation, it also regulates the growth and differentiation of embryonic stem cells, primordial germ cells, peripheral neurons, osteoblasts, adipocytes, and endothelial cells. Senturk et al. (1998) reviewed the role of leukemia inhibitory factor in human reproduction. LIF is crucial for successful implantation of the embryo in mice. LIF actions sre mediated through a high-affinity receptor complex composed of a low-affinity LIF binding chain (LIF receptor) and a high-affinity converter subunit, gp130. The high-affinity complex also binds a related cytokine, oncostatin M. Both LIF receptor and gp130 are members of a family of cytokine receptors that includes components of the receptors for the majority of hematopoietic cytokines and for cytokines that affect other systems, including the ciliary neurotrophic factor, growth hormone, and prolactin.
NCBI Summary:
This gene encodes a protein that belongs to the type I cytokine receptor family. This protein combines with a high-affinity converter subunit, gp130, to form a receptor complex that mediates the action of the leukemia inhibitory factor, a polyfunctional cytokine that is involved in cellular differentiation, proliferation and survival in the adult and the embryo. Mutations in this gene cause Schwartz-Jampel syndrome type 2, a disease belonging to the group of the bent-bone dysplasias. A translocation that involves the promoter of this gene, t(5;8)(p13;q12) with the pleiomorphic adenoma gene 1, is associated with salivary gland pleiomorphic adenoma, a common type of benign epithelial tumor of the salivary gland. Multiple splice variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]
General function
Receptor
Comment
Morita et al. (1999) showed that the combined actions of stem cell factor (SCF), LIF, and IGF-I are required for maximal inhibition of apoptosis in germ cells of fetal mouse ovaries.
Cellular localization
Plasma membrane
Comment
Ovarian function
Antral follicle growth, Follicle atresia, Germ cell development
Comment
Lack of FSH support enhances LIF-STAT3 signaling in granulosa cells of atretic follicles in cattle. Ilha GF et al. (2015) Subordinate follicles (SFs) of bovine follicular waves undergo atresia due to declining FSH concentrations; however, the signalling mechanisms have not been fully deciphered. We used an FSH-induced co-dominance model to determine the effect of FSH on signalling pathways in granulosa cells of the second-largest follicles (SF in control cows and co-dominant follicle (co-DF2) in FSH-treated cows). The SF was smaller than DF in control cows while diameters of co-DF1 and co-DF2 in FSH-treated cows were similar. The presence of cleaved CASP3 protein confirmed that granulosa cells of SFs, but not of DFs and co-DFs, were apoptotic. To determine the effect of FSH on molecular characteristics of the second-largest follicles, we generated relative variables for the second largest follicle in each cow. For this, variables of SF or co-DF2 were divided by the variables of the largest follicle DF or co-DF1 in each cow. There was higher transcript abundance of MAPK1/3 and AKT1/2/3 but lower abundance of phosphorylated MAPK3/1 in SF than co-DF2 granulosa cells. Abundance of mRNA and phosphorylated protein of STAT3 was higher in granulosa cells of control SF than FSH-treated co-DF2. SF granulosa cells had higher levels of LIFR and IL6ST transcripts, the two receptors involved in STAT3 activation. Further, lower transcript abundance of interleukin 6 receptor (IL6R), another receptor involved in STAT3 activation, indicated that STAT3 activation in SF granulosa cells could be mainly due to leukemia inhibitory factor (LIF) signalling. These results indicate that atresia due to lack of FSH is associated with activated LIF-STAT3 signalling in SF granulosa cells, as FSH treatment reversed such activation.//////////////////
Senturk et al. (1998) reviewed the role of LIF in reproduction and suggested that the rising follicular fluid LIF level around the time of ovulation indicates that LIF may play a role in ovulatory events, early embryonic development, and implantation. Apoptosis is responsible for primordial germ cell (PGC) attrition in the developing fetal ovary. In monolayer cultures of murine PGC, SCF and LIF independently promote PGC survival in vitro.
Expression regulated by
Comment
Ovarian localization
Oocyte, Granulosa
Comment
van Eijk et al. (1996) reported the expression of both components of the high-affinity leukaemia inhibitory factor receptor, LIFR beta and glycoprotein 130 (gp130) in human oocytes and individual in-vitro cultured preimplantation embryos by reverse transcription-polymerase chain reaction.
The multipotency of luteinizing granulosa cells collected from mature ovarian follicles. Kossowska-Tomaszczuk K et al. Graafian ovarian follicles consist of follicular fluid, one single mature oocyte, and several hundred thousands of granulosa cells (GCs). Until now, luteinizing GCs have been considered to be terminally differentiated, destined to undergo death after ovulation. Present concepts of luteal function, endocrine regulation of early pregnancy, and the recruitment of new ovarian follicles are all based on the cyclical renewal of the entire population of GCs. We now demonstrate that luteinizing GCs isolated from the ovarian follicles of infertile patients and sorted with flow cytometry based upon the presence of their specific marker, the follicle-stimulating hormone receptor (FSHR), can be maintained in culture over prolonged periods of time in the presence of the leukemia-inhibiting factor (LIF). Under those conditions the markers of GC function such as FSHR and aromatase gradually disappeared. POU5F1 (POU domain, class 5, homeobox 1), a typical stem cell marker, was expressed throughout the culture, but germ line cell markers such as nanog, vasa, and stellar were not. Mesenchymal lineage markers such as CD29, CD44, CD90, CD105, CD117, and CD166, but not CD73, were expressed by substantial subpopulations of GCs. The multipotency of a subset of GCs was established by in vitro differentiation into other cell types, otherwise not present within ovarian follicles, such as neurons, chondrocytes, and osteoblasts. Follicle-derived stem cells were also able to survive when transplanted into the backs of immunoincompetent mice, in vivo generating tissues of mesenchymal origin. The unexpected findings of multipotency of cells with prolonged lifespans originating from ovarian follicles are likely to have a significant impact on evolving theories in ovarian pathophysiology, particularly with reference to ovarian endometriosis and ovarian cancer. STEM CELLS 2009;27:210-219.
A NOVEL THREE-DIMENSIONAL CULTURE SYSTEM ALLOWS PROLONGED CULTURE OF FUNCTIONAL HUMAN GRANULOSA CELLS AND MIMICS THE OVARIAN ENVIRONMENT. Kossowska-Tomaszczuk K et al. The development of techniques allowing the growth of primordial follicles to mature follicles in vitro has much potential for both reproductive medicine and developmental research. However, human primordial and preantral follicles fail to grow after isolation from the surrounding ovarian stroma. Granulosa cells (GCs), which normally undergo apoptosis after ovulation, contain a subpopulation of ovarian follicular cells remaining viable in vitro over prolonged time periods when cultured in the presence of leukaemia inhibiting factor (LIF). However, when cultured as monolayers, they progressively lose all their characteristics, such as follicle-stimulating hormone receptor (FSHR) and cytochrome P450-aromatase. Here, we describe a three-dimensional (3D) culture system containing type I collagen, which, together with LIF, allowed the survival and growth of a subpopulation of GCs isolated from mature ovarian follicles and supported them to proliferate into spherical structures exhibiting steroidogenic capacity, as demonstrated by P450-aromatase and 3-hydroxysteroid dehydrogenase. After transplantation into the ovaries of immuno-deficient mice, these cells became localized preferentially within antral follicles and the prolonged expression of FSHR was confirmed as well. With this optimization of the culture conditions an environment was created, which acts as a niche closely mimicking the development of early ovarian follicles in vitro.
Follicle stages
Preovulatory
Comment
Immunocytochemical detection and RT-PCR expression of leukaemia inhibitory factor and its receptor in human fetal and adult ovaries.
Abir R, et a .
The ability to mature human primordial follicles in vitro would assist fertility restoration. However, the signals initiating growth of primordial follicles are unknown. Growth factors such as leukaemia inhibitory factor (LIF) may play a role in this process. To investigate the expression of LIF and its receptor in early developing follicles, nine ovarian samples from adolescents/adults aged 13-43 years and 23 ovaries from human fetuses aged 19-33 gestational weeks were immediately fixed or frozen. The fixed samples were prepared for a study of immunocytochemical staining of LIF and its two receptor units (LIF-R and gp 130). mRNA was extracted from the frozen ovarian samples, and the expression of LIF, LIF-R and gp 130 was investigated by RT-PCR. Products were resolved by 10% polyacrylamide gel electrophoresis and image analysis. There was strong to moderate immunocytochemical staining for LIF and LIF-R in oocytes from the primordial follicular stages onwards, and very weak to moderate staining for gp 130. LIF-R was also detected in granulosa cells of primary and secondary follicles from adolescents/adults. Transcripts of LIF, LIF-R and gp 130 RNA were identified by RT-PCR in all samples. The immunocytochemical staining and mRNA expression of LIF and its receptor are consistent with the concept that LIF might be involved in growth initiation of human primordial follicles through its receptor.