LIF (leukemia inhibitory factor) is a widely expressed pleiotropic member of the IL-6 family of cytokines (1-3). Mature mouse LIF is expressed as a highly and variably glycosylated 32-62 kDa monomer that shares 78%, 91%, 80%, 76%, and 78% aa sequence identity with human, rat, canine, bovine, and porcine LIF, respectively (4). LIF functions through a heterodimeric receptor complex containing a ligand-binding subunit, LIF R alpha /CD118, and a signal transducing subunit, gp130 (2, 4, 5). gp130 also serves as a subunit of the receptor complexes for Oncostatin M, Cardiotrophin-1, CNTF, IL-6, IL-11, and IL-27 (2, 5). A soluble form of mouse LIF R alpha can be generated by alternative splicing (6). Depending on the cells and their context, LIF either opposes or favors differentiation (2, 7). LIF produced by the uterine endometrium supports successful implantation of the embryo, promotes proliferation and maintenance of pluripotency in embryonic stem cells, and favors proliferation of progenitor cell types such as hematopoietic stem cells (2, 5, 7). However, excess LIF blocks differentiation of embryoid bodies, indicating the importance of LIF regulation (2, 5). LIF is produced by activated CD4+
T cells and is required by the thymic epithelium to support T cell maturation (2, 3). Its expression is upregulated by neuronal injury, and it promotes motor neuron survival and oligodendrocyte myelination (2, 3, 8). It is produced by the adrenal cortex and likely enhances adrenal production of cortisol and aldosterone (9). LIF can also function as an autocrine growth factor in some pancreatic cancers, but it induces differentiation in the myeloid leukemic cell line M1 (1, 10). Tumor cell-derived LIF can also induce formation of immunosuppressive tumor-associated macrophages (11). LIF promotes endometrial remodeling and differentiation of adipocytes and cardiac smooth muscle cells (2, 3, 12). It promotes regulatory T cell and inhibits Th17 cell differentiation, thus down-regulating inflammation and contributing to immune tolerance during pregnancy and in the nervous system (2, 3, 5, 7).
- Moreau, J.F. et al. (1988) Nature 336:690.
- Trouillas, M. et al. (2009) Eur. Cytokine Netw. 20:51.
- Metcalfe, S.M. (2011) Genes Immun. 12:157.
- Gearing, D.P. et al. (1987) EMBO J. 6:3995.
- Cheng, J.G. et al. (2001) Proc. Natl. Acad. Sci. USA 98:8680.
- Tomida, M. et al. (1993) FEBS lett. 334:193.
- Paiva, P. et al. (2009) Cytokine Growth Factor Rev. 20:319.
- Slaets, H. et al. (2010) Trends Mol. Med. 16:493.
- Bamberger, A.M. et al. (2000) Mol. Cell. Endocrinol. 162:145.
- Kamohara, H. et al. (2007) Int. J. Oncol. 30:977.
- Duluc, D. et al. (2007) Blood 110:4319.
- Zouein, F.A. et al. (2013) Eur. Cytokine Netw. 24:11.