The effect of leukemia inhibitory factor (LIF) on trophoblast differentiation: a potential role in human implantation.

Abstract

Leukemia inhibitory factor (LIF) is a multifunctional glycoprotein strongly associated with normal implantation in the mouse. We have recently determined that LIF is expressed in the human endometrium in a menstrual cycle dependent manner. Maximal expression is observed between days 19 and 25 of the menstrual cycle, coinciding with the time of human implantation. In this study we have utilized purified cultures of human cytotrophoblasts to examine the effects of LIF on several morphologic and biochemical markers of the trophoblastic differentiation. We purified human cytotrophoblasts from term placentae and cultured them with and without LIF (10 ng/mL). The secretion of human CG, oncofetal fibronectin, and progesterone were measured at 24, 48, 72, and 96 h. Northern blot analysis was used to assess messenger RNA (mRNA) expression of beta hCG and oncofetal fibronectin. We found that LIF markedly decreased trophoblast production of hCG protein at 72 and 96 h, as well as expression of beta hCG mRNA. LIF also significantly increased the expression of oncofetal fibronectin mRNA and secretion of the protein. LIF did not affect steroidogenic activity of cultured trophoblasts, as determined by progesterone production. These biochemical changes are characteristic of cytotrophoblast differentiation toward an anchoring extravillous phenotype. Thus, LIF appears to be an important regulator of human embryonic implantation by directly modulating trophoblast differentiation.

Recombinant human leukemia inhibitory factor does not improve implantation and pregnancy outcomes after assisted reproductive techniques in women with recurrent unexplained implantation failure

“…Leukemia inhibitory factor (LIF) regulates the differentiation of the endometrium and may also promote development and implantation of the blastocyst (1)(2)(3)(4)(5)(6)(7). Evidence suggests that dysfunction of LIF expression may contribute to recurrent implantation failure (8)(9)(10)(11).…”

Locally elevated leukemia inhibitory factor in the inflamed fallopian tube resembles that found in tubal pregnancy

“…The effects of LIF in human reproduction were not different from those of mice. The expression of LIF in human endometria is dependent on cellular localizations and menstrual stages and reaches the peak values on luminal epithelium during the implantation window (4)(5)(6)(7)(8)(9)(10). Aberrant expression of LIF has been strongly associated with human infertility (11,12,22).…”

“…The anti-LIF antibody detected a predominant band at 45 kDa. Chronic salpingitis tissues (1,4), normal fallopian tubes (2,3), fallopian tubal tissues in implantation site (5,7), fallopian tubal tissues in nonimplantation site (6,8).…”

“…Leukemia inhibitory factor is expressed in the human endometrium in a menstrual cycle-dependent manner. The increased LIF messenger RNA levels are observed in the midsecretory phase and peak at the putative implantation window (4)(5)(6)(7)(8)(9)(10). Leukemia inhibitory factor was detected in the uterine flushings during the time of expected implantation in fertile women; in contrast, the LIF concentration of the uterine flushings from women with unexplained infertility was significantly reduced (11).…”

Oncostatin M and leukaemia inhibitory factor trigger signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1/2 pathways but result in heterogeneous cellular responses in trophoblast cells

“…It has been reported that trophoblast invasion and placental development are regulated by LIF (Bischof et al 1995;Sharkey et al 1995;Nachtigall et al 1996). In particular, our group has shown that LIF enhances the invasiveness of trophoblast cells by activation of STAT3 and downregulation of tissue-specific inhibitors of metalloproteinase (TIMP)-1 Poehlmann et al 2005).…”