Leukemia Inhibitory Factor (LIF) is a pleiotropic cytokine1,2 of the IL-6 family. Although named for its ability to inhibit proliferation of the mouse myeloid leukemic cell line M1 by inducing differentiation,3 it also promotes survival and proliferation of other types of cells.1,2,4 An earlier report that LIF promotes the survival of primordial germ cells5 suggested a role in reproduction. This work has been extended,6-8 and an essential role for LIF in implantation has been demonstrated.9
Using LIF knockout mice, Stewart et al.9 showed that homozygous LIF-deficient females failed to become pregnant when mated to wild-type males, though live blastocysts could be recovered from the uterine lumen of these females four days after mating to heterozygous or homozygous LIF-deficient males. These viable blastocysts implanted and reached term when transferred to pseudopregnant wild-type females, indicating that failure to implant was the cause of failure to become pregnant.
Does LIF play a role in human implantation? Three lines of evidence are consistent with such a role i) LIF mRNA and LIF protein levels in the endometrium peak at the time of implantation.10-12 ii) LIF receptor beta (LIF R) is expressed in endometrial tissue in both the proliferative and secretory phases of the menstrual cycle.12 iii) Secretion of LIF was lower in cultures of human endometrial explants from women with repeated failure to implant and from women with unexplained infertility.12-14
The menstrual cycle dependence of endometrial LIF mRNA and LIF protein suggests that the LIF gene is controlled by progesterone.15 Arici et al.16 could not, however, demonstrate a direct effect of estradiol or progesterone on LIF mRNA or LIF protein levels in cultured endometrial cells. In contrast, IL-1, TNF-alpha, PDGF, EGF, and TGF-beta were potent inducers of LIF expression. The fact that RU486 inhibits LIF production in decidual explants in culture14 suggests that progesterone action on the endometrium may be required for LIF expression.
LIF R was present in human blastocysts in a stage-dependent manner, while LIF protein was not expressed at any stage examined.12,17 These data, together with work cited earlier, are consistent with LIF protein of endometrial origin acting on blastocysts at the time of implantation. Studies in a mouse model suggest that LIF may have an embryotrophic effect,18 but recombinant human LIF did not enhance in vitro human blastocyst formation.19
LIF R is present in human placenta together with gp130, the signal transducing subunit of the IL-6 family receptors, while LIF protein is not.20-22 These findings are consistent with a role for LIF in trophoblast differentiation and implantation.