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Gene Review

LIF  -  leukemia inhibitory factor

Homo sapiens

Synonyms: CDF, D factor, DIA, Differentiation-stimulating factor, HILDA, ...
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Disease relevance of LIF


High impact information on LIF

  • We show that LIF production is associated with type 2 T-helper cells, is upregulated by IL-4 and progesterone and is downregulated by IL-12, IFN-gamma and IFN-alpha [7].
  • We also show a decreased production of LIF, IL-4 and IL-10 by decidual T cells of women with unexplained recurrent abortions in comparison with that of women with normal gestation [7].
  • The defective production of LIF and/or type 2 T-helper cytokines may contribute to the development of unexplained recurrent abortions [7].
  • We demonstrate here that purified, recombinant LIF can substitute for DIA in the maintenance of totipotent ES cell lines that retain the potential to form chimaeric mice [8].
  • In addition to classic hematopoietic and neuronal actions, LIF plays a critical role in several endocrine functions including the utero-placental unit, the hypothalamo-pituitary-adrenal axis, bone cell metabolism, energy homeostasis, and hormonally responsive tumors [9].

Chemical compound and disease context of LIF


Biological context of LIF


Anatomical context of LIF


Associations of LIF with chemical compounds

  • Treatment with the reversible PI3K inhibitor, LY294002, or more specific inhibition of class I(A) PI3K via regulated expression of dominant negative Deltap85, led to a reduction in the ability of LIF to maintain self-renewal, with cells concomitantly adopting a differentiated morphology [22].
  • LIF is a glycoprotein secreted by a number of different cell types in vitro [4].
  • The structure of Leukaemia Inhibitory Factor (LIF) and Oncostatin M (OSM) receptors is not completely resolved [23].
  • Using alanine-scanning mutagenesis of the Ig-like domain, we mapped a LIF binding site at its carboxyl terminus, mainly involving residue Phe-328 [24].
  • While leukemia inhibitory factor (LIF) maintains pluripotency in mouse ES cells, retinoic acid and other nuclear hormones induce neuro-glial differentiation in mouse and human ES cells in culture [25].

Physical interactions of LIF

  • The region of hLIF most important for binding to the hLIF-R is composed of residues from the amino terminus of the D-helix, carboxyl terminus of the B-helix, and C-D loop [16].
  • Residues in hLIF from both the A- and C-helices are involved in binding the gp130 co-receptor [16].
  • Only LIF elicited strong tyrosine phosphorylation and specific DNA-binding activity of STAT3 [26].
  • TGF-beta and rIL-1 alpha also interacted in a synergistic fashion to further increase LIF elaboration [27].
  • The identity of this LIF binding component with the Man-6-P/insulin-like growth factor-II receptor (Man-6-P/IGFII-R) was supported by several findings [28].

Enzymatic interactions of LIF

  • We found that gp130 fusion proteins were phosphorylated exclusively on Ser-782 by LIF- and growth factor-stimulated 3T3-L1 cell extracts [29].
  • Moreover, endogenous STAP-2 was phosphorylated at Tyr250 following LIF stimulation of murine M1 cell line [30].

Regulatory relationships of LIF

  • A second region of hLIF that includes residues from the carboxyl terminus of the D-helix and A-B loop also had a weak influence on hLIF-R binding [16].
  • Stat3 activation was constitutive in SEKI cells and induced on treatment of 293 cells with LIF [1].
  • It is concluded that OSM can induce inflammatory reaction not only directly but also via LIF production by tumor cells [5].
  • We find that SOCS-3 is expressed in the neuronal cell lines SN56 and IMR32 and negatively regulates LIF-stimulated neuronal gene expression [31].
  • Thus, LIF may regulate by a gp130-dependent pathway macrophage-mediated procoagulant function in diverse pathological states involving inflammation and thrombosis and seems to serve as an important mediator at the interface between these processes [32].

Other interactions of LIF

  • Furthermore, anti-gp130 mAb completely inhibited the proliferation of the cells induced by OSM, LIF, as well as IL-6 [33].
  • These cells release IL-6 but not OSM or LIF into the culture supernatant during short-term culture [33].
  • Thus, whereas LIF and CNTF have clear roles in maintenance and following trauma, it is unclear which of the cytokines is involved in nervous system development [18].
  • Molecular modeling of the complex of LIF with the Ig-like domain of LIFR provides a clue for the superadditivity of the D214A/F284A double mutation [34].
  • Interestingly, binding of LIF to type 1 receptor was not affected, corroborating the notion that in this case gp130 mostly behaves as a converter protein rather than a binding receptor [35].

Analytical, diagnostic and therapeutic context of LIF

  • LIF content in culture supernatants was assayed by a specific ELISA (sensitivity: 25 pg/ml) [5].
  • Leukaemia inhibitory factor (LIF) and interleukin (IL)-6 are members of a cytokine group that share a common signal transducer gp130 and induce pleiotropic biological effects in cells of diverse lineage [32].
  • Anti-LIF receptor and anti-gp130 antibodies attenuated the effect of LIF on TF expression as assayed by both bioassay and flow-cytometry [32].
  • In the control group LIF, CNTF and IL-11 were measurable in 8.3%, 33.3% and 8.3% respectively [36].
  • The expression of oncostatin M and leukemia inhibitory factor (LIF), JAK-STAT activators and members of the interleukin-6 family of cytokines, were examined in a series of primary ovarian carcinomas using immunohistochemistry [37].


  1. The human hepatocyte growth factor (HGF) gene is transcriptionally activated by leukemia inhibitory factor through the Stat binding element. Tomida, M., Saito, T. Oncogene (2004) [Pubmed]
  2. Differential effects of oncostatin M and leukaemia inhibitory factor expression in astrocytoma cells. Kasza, A., Rogowski, K., Kilarski, W., Sobota, R., Bernas, T., Dobrucki, J., Travis, J., Koj, A., Bugno, M., Kordula, T. Biochem. J. (2001) [Pubmed]
  3. Oncostatin M-specific receptor mediates inhibition of breast cancer cell growth and down-regulation of the c-myc proto-oncogene. Liu, J., Spence, M.J., Wallace, P.M., Forcier, K., Hellström, I., Vestal, R.E. Cell Growth Differ. (1997) [Pubmed]
  4. Crystallization and preliminary X-ray analysis of leukemia inhibitory factor. Betzel, C., Visanji, M., Dauter, Z., Fourme, R., Weber, W., Marnitz, U., Boone, T., Pope, J., Miller, J., Hawkins, N. FEBS Lett. (1993) [Pubmed]
  5. Modulation of LIF expression in human melanoma cells by oncostatin M. Heymann, D., Blanchard, F., Raher, S., De Groote, D., Godard, A. Immunol. Lett. (1995) [Pubmed]
  6. Tumor-associated leukemia inhibitory factor and IL-6 skew monocyte differentiation into tumor-associated macrophage-like cells. Duluc, D., Delneste, Y., Tan, F., Moles, M.P., Grimaud, L., Lenoir, J., Preisser, L., Anegon, I., Catala, L., Ifrah, N., Descamps, P., Gamelin, E., Gascan, H., Hebbar, M., Jeannin, P. Blood (2007) [Pubmed]
  7. Defective production of both leukemia inhibitory factor and type 2 T-helper cytokines by decidual T cells in unexplained recurrent abortions. Piccinni, M.P., Beloni, L., Livi, C., Maggi, E., Scarselli, G., Romagnani, S. Nat. Med. (1998) [Pubmed]
  8. Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells. Williams, R.L., Hilton, D.J., Pease, S., Willson, T.A., Stewart, C.L., Gearing, D.P., Wagner, E.F., Metcalf, D., Nicola, N.A., Gough, N.M. Nature (1988) [Pubmed]
  9. Leukemia-inhibitory factor-neuroimmune modulator of endocrine function. Auernhammer, C.J., Melmed, S. Endocr. Rev. (2000) [Pubmed]
  10. Leukemia inhibitory factor: a novel bone-active cytokine. Reid, L.R., Lowe, C., Cornish, J., Skinner, S.J., Hilton, D.J., Willson, T.A., Gearing, D.P., Martin, T.J. Endocrinology (1990) [Pubmed]
  11. Leukemia inhibitory factor binds to human breast cancer cells and stimulates their proliferation. Estrov, Z., Samal, B., Lapushin, R., Kellokumpu-Lehtinen, P., Sahin, A.A., Kurzrock, R., Talpaz, M., Aggarwal, B.B. J. Interferon Cytokine Res. (1995) [Pubmed]
  12. Stimulation of HIV replication in mononuclear phagocytes by leukemia inhibitory factor. Broor, S., Kusari, A.B., Zhang, B., Seth, P., Richman, D.D., Carson, D.A., Wachsman, W., Lotz, M. J. Acquir. Immune Defic. Syndr. (1994) [Pubmed]
  13. Differentiation factor/leukemia inhibitory factor protection against lethal endotoxemia in mice: synergistic effect with interleukin 1 and tumor necrosis factor. Alexander, H.R., Wong, G.G., Doherty, G.M., Venzon, D.J., Fraker, D.L., Norton, J.A. J. Exp. Med. (1992) [Pubmed]
  14. AIDS-associated Kaposi's sarcoma (KS) cells express oncostatin M (OM)-specific receptor but not leukemia inhibitory factor/OM receptor or interleukin-6 receptor. Complete block of OM-induced KS cell growth and OM binding by anti-gp130 antibodies. Murakami-Mori, K., Taga, T., Kishimoto, T., Nakamura, S. J. Clin. Invest. (1995) [Pubmed]
  15. The box-1 region of the leukemia inhibitory factor receptor alpha-chain cytoplasmic domain is sufficient for hemopoietic cell proliferation and differentiation. Zhang, Y., Willson, T., Metcalf, D., Cary, D., Hilton, D.J., Clark, R., Nicola, N.A. J. Biol. Chem. (1998) [Pubmed]
  16. Characterization of the receptor binding sites of human leukemia inhibitory factor and creation of antagonists. Hudson, K.R., Vernallis, A.B., Heath, J.K. J. Biol. Chem. (1996) [Pubmed]
  17. Dual oncostatin M (OSM) receptors. Cloning and characterization of an alternative signaling subunit conferring OSM-specific receptor activation. Mosley, B., De Imus, C., Friend, D., Boiani, N., Thoma, B., Park, L.S., Cosman, D. J. Biol. Chem. (1996) [Pubmed]
  18. Cytokines which signal through the LIF receptor and their actions in the nervous system. Murphy, M., Dutton, R., Koblar, S., Cheema, S., Bartlett, P. Prog. Neurobiol. (1997) [Pubmed]
  19. FR901228, an inhibitor of histone deacetylases, increases the cellular responsiveness to IL-6 type cytokines by enhancing the expression of receptor proteins. Blanchard, F., Kinzie, E., Wang, Y., Duplomb, L., Godard, A., Held, W.A., Asch, B.B., Baumann, H. Oncogene (2002) [Pubmed]
  20. Immunohistochemical analysis of the IL-6 family of cytokines and their receptors in benign, hyperplasic, and malignant human prostate. Royuela, M., Ricote, M., Parsons, M.S., García-Tuñón, I., Paniagua, R., de Miguel, M.P. J. Pathol. (2004) [Pubmed]
  21. Distinct effects of Broncho-Vaxom (OM-85 BV) on gp130 binding cytokines. Roth, M., Block, L.H. Thorax (2000) [Pubmed]
  22. Regulation of embryonic stem cell self-renewal by phosphoinositide 3-kinase-dependent signaling. Paling, N.R., Wheadon, H., Bone, H.K., Welham, M.J. J. Biol. Chem. (2004) [Pubmed]
  23. Leukemia inhibitory factor (LIF) and oncastsin M (OSM) high affinity binding require additional receptor subunits besides GP130 and GP190. Heymann, D., Godard, A., Raher, S., Bentouimou, N., Blanchard, F., Cherel, M., Hallet, M.M., Jacques, Y. Cytokine (1996) [Pubmed]
  24. Mutations in the immunoglobulin-like domain of gp190, the leukemia inhibitory factor (LIF) receptor, increase or decrease its affinity for LIF. Bitard, J., Daburon, S., Duplomb, L., Blanchard, F., Vuisio, P., Jacques, Y., Godard, A., Heath, J.K., Moreau, J.F., Taupin, J.L. J. Biol. Chem. (2003) [Pubmed]
  25. 15-Deoxy-delta12,14-prostaglandin J2 regulates leukemia inhibitory factor signaling through JAK-STAT pathway in mouse embryonic stem cells. Rajasingh, J., Bright, J.J. Exp. Cell Res. (2006) [Pubmed]
  26. Leukemia inhibitory factor triggers activation of signal transducer and activator of transcription 3, proliferation, invasiveness, and altered protease expression in choriocarcinoma cells. Fitzgerald, J.S., Tsareva, S.A., Poehlmann, T.G., Berod, L., Meissner, A., Corvinus, F.M., Wiederanders, B., Pfitzner, E., Markert, U.R., Friedrich, K. Int. J. Biochem. Cell Biol. (2005) [Pubmed]
  27. Cytokine-cytokine synergy and protein kinase C in the regulation of lung fibroblast leukemia inhibitory factor. Elias, J.A., Zheng, T., Whiting, N.L., Marcovici, A., Trow, T.K. Am. J. Physiol. (1994) [Pubmed]
  28. The mannose 6-phosphate/insulin-like growth factor II receptor is a nanomolar affinity receptor for glycosylated human leukemia inhibitory factor. Blanchard, F., Raher, S., Duplomb, L., Vusio, P., Pitard, V., Taupin, J.L., Moreau, J.F., Hoflack, B., Minvielle, S., Jacques, Y., Godard, A. J. Biol. Chem. (1998) [Pubmed]
  29. Phosphorylation of human gp130 at Ser-782 adjacent to the Di-leucine internalization motif. Effects on expression and signaling. Gibson, R.M., Schiemann, W.P., Prichard, L.B., Reno, J.M., Ericsson, L.H., Nathanson, N.M. J. Biol. Chem. (2000) [Pubmed]
  30. Leukemia inhibitory factor-induced phosphorylation of STAP-2 on tyrosine-250 is involved in its STAT3-enhancing activity. Sekine, Y., Tsuji, S., Ikeda, O., Kakisaka, M., Sugiyama, K., Yoshimura, A., Matsuda, T. Biochem. Biophys. Res. Commun. (2007) [Pubmed]
  31. Independent roles of SOCS-3 and SHP-2 in the regulation of neuronal gene expression by leukemia inhibitory factor. Bartoe, J.L., Nathanson, N.M. Brain Res. Mol. Brain Res. (2002) [Pubmed]
  32. Leukaemia inhibitory factor enhances tissue factor expression in human monocyte-derived macrophages: a gp130-mediated mechanism. Meisel, S.R., Shimon, I., Edgington, T.S., Melmed, S., Cercek, B., Shah, P.K. Br. J. Haematol. (1999) [Pubmed]
  33. Oncostatin M, leukemia inhibitory factor, and interleukin 6 induce the proliferation of human plasmacytoma cells via the common signal transducer, gp130. Nishimoto, N., Ogata, A., Shima, Y., Tani, Y., Ogawa, H., Nakagawa, M., Sugiyama, H., Yoshizaki, K., Kishimoto, T. J. Exp. Med. (1994) [Pubmed]
  34. Leukemia inhibitory factor (LIF), cardiotrophin-1, and oncostatin M share structural binding determinants in the immunoglobulin-like domain of LIF receptor. Plun-Favreau, H., Perret, D., Diveu, C., Froger, J., Chevalier, S., Lelièvre, E., Gascan, H., Chabbert, M. J. Biol. Chem. (2003) [Pubmed]
  35. Identification of a gp130 cytokine receptor critical site involved in oncostatin M response. Olivier, C., Auguste, P., Chabbert, M., Lelièvre, E., Chevalier, S., Gascan, H. J. Biol. Chem. (2000) [Pubmed]
  36. Circulating IL-6-type cytokines and sIL-6R in patients with multiple myeloma. Wierzbowska, A., Urbańska-Ryś, H., Robak, T. Br. J. Haematol. (1999) [Pubmed]
  37. Coexpression of oncostatin M and its receptors and evidence for STAT3 activation in human ovarian carcinomas. Savarese, T.M., Campbell, C.L., McQuain, C., Mitchell, K., Guardiani, R., Quesenberry, P.J., Nelson, B.E. Cytokine (2002) [Pubmed]
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