LIF in Reproduction

Leukemia Inhibitory Factor (LIF) is a pleiotropic cytokine^1,2 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.

References

1. Hilton, D.J. & N.M. Gough (1991) J. Cell Biochem. 46:21.
2. Hilton, D.J. (1992) Trends Biochem. Sci. 17:72.
3. Hilton, D.J. et al. (1988) J. Biol. Chem. 263:9238.
4. Metcalf, D. et al. (1990) Blood 76:50.
5. De Felici, M. & S. Dolci (1991) Dev. Biol. 147:281.
6. Cheng, L. et al. (1994) Development 120:3145.
7. Pesce, M. et al. (1993) Development 118:1089.
8. De Miguel, M.P. et al. (1996) Endocrinology 137:1885.
9. Stewart, C.W. et al. (1992) Nature 359:76.
10. Charnock-Jones, D.S. et al. (1994) J. Reprod. Fertil. 101:421.
11. Vogiagis, D. et al. (1996) J. Endocrinol. 148:95.
12. Cullinan, E.B. et al. (1996) Proc. Natl. Acad. Sci. USA 93:3115.
13. Delage, G. et al. (1995) Hum. Reprod. 10(9):2483.
14. Chaouat, G. et al. (1995) Hum. Reprod. 10(2):55.
15. Ace, C.I. & W.C. Okulicz (1995) Mol. Cell Endocrinol. 115:95.
16. Arici, A. et al. (1995) J. Clin. Endocrinol. Metab.80:1908.
17. Sharkey, A.M. (1995) Biol. Reprod. 53:955.
18. Lavranos, T.C. et al. (1995) J. Reprod. Fertil. 105:331.
19. Juriscova, A. et al. (1995) Fert. Steril. 64:999.
20. King, A. et al. (1995) Cytokine 7:364.
21. Kojima, K. et al. (1995) Hum. Reprod. 10(7):1907.
22. Nachtigall, M.J. et al. (1996) J. Clin. Endocrinol. Metab. 81:801.