Clomiphene citrate versus letrozole: molecular analysis of the endometrium in women with polycystic ovary syndrome.

OBJECTIVE: To compare the effect of clomiphene citrate (CC) and letrozole on endometrial receptivity in women with polycystic ovary syndrome (PCOS). DESIGN: A randomized controlled trial. SETTING: University teaching hospital. PATIENT(S): Ten anovulatory women with PCOS and 5 fertile ovulatory women. INTERVENTION(S): Patients received 2.5 mg of letrozole on cycle days 3-7 (5 patients, 1 cycle) or 50 mg of CC on cycle days 5-9 (5 patients, 1 cycle). MAIN OUTCOME MEASURE(S): Serum estrogen (E) and progesterone (P) endometrial protein and messenger RNA (mRNA) expression of leukemia inhibitory factor (LIF), dickkhopf homolog 1 (DKK-1), fibroblast growth factor 22 (FGF-22), and endometrial mRNA expression of LIF/GP130 receptor (LIFR). RESULT(S): No statistically significant differences were observed between groups compared with fertile ovulatory women when serum E and P were examined, or between body mass index (BMI), and cycle day at time of biopsy. Letrozole increased mRNA expression of LIF, DKK1, LIFR, and FGF-22, whereas CC only increased endometrial mRNA expression of LIF. Letrozole mRNA expression directly translated into increased protein expression of like genes in the endometrium. The CC protein expression of DKK-1 was significantly decreased compared with controls. CONCLUSION(S): Letrozole positively influences a number of markers of endometrial receptivity compared with CC.

Leukemia inhibitory factor protein and receptors are expressed in the bovine adrenal cortex and increase cortisol and decrease adrenal androgen release.

The release of adrenal steroids during acute stress is primarily regulated by adrenocorticotropic hormone (ACTH). In contrast, during chronic inflammatory stress additional factors are involved in regulating adrenal function. Leukemia inhibitory factor (LIF) is a pleiotropic cytokine that increases ACTH release from the pituitary. In addition, LIF and LIF receptors (LIFR) are expressed in the human adrenal cortex and the human adrenocortical tumor cell line H295R. Furthermore, LIF increases basal and ACTH-stimulated cortisol release from H295R cells. However, the expression of LIF and LIFR in non-human adrenal glands and the effects of LIF on the release of cortisol from adrenal cells of non-human species have not been determined. Furthermore, the effects of LIF on adrenal androgen release from all species are unknown. In this study, immunohistochemistry, Western blots, RT-PCR, and nucleotide sequencing was utilized to demonstrate that LIF and its receptor are expressed throughout the bovine adrenal cortex. Although LIF did not modify basal cortisol release from dispersed cells isolated from the bovine adrenal zona fasciculate, this cytokine increased ACTH-stimulated release of cortisol from these cells in a manner dependent on the LIF concentration and exposure interval. In contrast, LIF in a concentration-dependent and time-dependent manner decreased basal and ACTH-stimulated adrenal androgen release from dispersed cells isolated from the bovine adrenal zona reticularis. Because LIF release increases during inflammatory stress and this cytokine stimulates adrenal cortisol release and inhibits adrenal androgen release, this cytokine may play an important role in regulating the release of adrenal steroids during inflammatory stress.

Transregulation of leukemia inhibitory [corrected] factor receptor expression and function by growth factors in neuroblastoma cells.

The cytokines that signal through the leukemia inhibitory factor (LIF) receptor are members of the neuropoietic cytokine family and have varied and numerous roles in the nervous system. In this report, we have determined the effects of growth factor stimulation on LIF receptor (LIFR) expression and signal transduction in the human neuroblastoma cell line NBFL. We show here that stimulation of NBFL cells with either epidermal growth factor or fibroblast growth factor decreases the level of LIFR in an extracellular signal-regulated kinase (Erk)1/2-dependent manner and that this down-regulation is due to an increase in the apparent rate of lysosomal LIFR degradation. Growth factor-induced decreases in LIFR level inhibit both LIF-stimulated phosphorylation of signal transducers and activators of transcription 3 and LIFR-mediated gene induction. We also show that Ser1044 of LIFR, which we have previously shown to be phosphorylated by Erk1/2, is required for the inhibitory effects of growth factors. Neurons are exposed to varying combinations and concentrations of growth factors and cytokines that influence their growth, development, differentiation, and repair in vivo. These findings demonstrate that LIFR expression and signaling in neuroblastoma cells can be regulated by growth factors that are potent activators of the mitogen-activated protein kinase pathway, and thus illustrate a fundamental mechanism that underlies crosstalk between receptor tyrosine kinase and neuropoietic cytokine signaling pathways.

OSM, LIF, its receptors, and its relationship with the malignance in human breast carcinoma (in situ and in infiltrative).

IL-6 cytokine family is composed by several members. IL-6, LIF, and gp130 have been associated with cancer progression. Cytokines play an important role in tumoral growth, invasion of the vessels and development of metastases. Immunoexpressions of LIF, OSM, LIFRbeta and OSMRbeta were studied in benign breast lesion, in situ and infiltrating tumors by Western blot and immunohistochemistry. Percentages of positive samples to OSM, LIF and OSMRbeta were higher in in situ carcinoma than in benign diseases and even higher in infiltrating tumors. gp130-positive samples was higher in infiltrating tumor than in benign diseases. All samples studied were LIFRbeta-positive. Infiltrating tumors showed the most intense immunostaining to LIFRbeta, OSM and OSMRbeta; comparing present results revealed an association between the expression of these proteins and increasing malignancy. In conclusions, development of breast tumor increases the expression of OSM, LIF, OSMRbeta, LIFRbeta and gp130, and this expression may be associated with the malignancy. IL-6 family exert their action through transducer receptor gp130, and gp130 expression increase with malignance, it might be a crucial point in the development of infiltrative adenocarcinoma. The secretion of OSM and LIF by both epithelial and stromal (paracrine manner) cells seems to promote tumor growth.

Leukemia inhibitory factor deficiency modulates the immune response and limits autoimmune demyelination: a new role for neurotrophic cytokines in neuroinflammation.

The neurotrophic cytokines ciliary neurotrophic factor and leukemia inhibitory factor (LIF) play a key role in neuronal and oligodendrocyte survival and as protective factors in neuroinflammation. To further elucidate the potential of endogenous LIF in modulating neuroinflammation, we studied myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in LIF knockout mice (LIF(-/-) mice). In the late phase of active myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis, LIF(-/-) mice exhibited a markedly milder disease course. The inflammatory infiltrate in LIF(-/-) mice was characterized by an increase in neutrophilic granulocytes early and fewer infiltrating macrophages associated with less demyelination later in the disease. In good correlation with an effect of endogenous LIF on the immune response, we found an Ag-specific T cell-priming defect with impaired IFN-gamma production in LIF(-/-) mice. On the molecular level, the altered recruitment of inflammatory cells is associated with distinct patterns of chemokine production in LIF(-/-) mice with an increase of CXCL1 early and a decrease of CCL2, CCL3, and CXCL10 later in the disease. These data reveal that endogenous LIF is an immunologically active molecule in neuroinflammation. This establishes a link between LIF and the immune system which was not observed in the ciliary neurotrophic factor knockout mouse.

LIF-mediated control of embryonic stem cell self-renewal emerges due to an autoregulatory loop.

Stem cells convert graded stimuli into all-or-nothing cell-fate responses. We investigated how embryonic stem cells (ESCs) convert leukemia inhibitory factor (LIF) concentration into an all-or-nothing cell-fate decision (self-renewal). Using a combined experimental/computational approach we demonstrate unexpected switch-like (on/off) signaling in response to LIF. This behavior emerges over time due to a positive feedback loop controlling transcriptional expression of LIF signaling pathway components. The autoregulatory loop maintains robust pathway responsiveness ("on") at sufficient concentrations of exogenous LIF, while autocrine signaling and low concentrations of exogenous LIF cause ESCs to adopt the weakly responsive ("off") state of differentiated cells. We demonstrate that loss of ligand responsiveness is reversible and precedes loss of the ESC transcription factors Oct4 and Nanog, suggesting an early step in the hierarchical control of differentiation. While endogenously produced ligands were insufficient to sustain the "on" state, they buffer it, influencing the timing of differentiation. These results demonstrate a novel switch-like behavior, which establishes the LIF threshold for ESC self-renewal.