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Review
. 2015 Oct;26(5):533-44.
doi: 10.1016/j.cytogfr.2015.07.001. Epub 2015 Jul 4.

Leukemia inhibitory factor (LIF)

Nicos A Nicola  1 , Jeffrey J Babon  2
Affiliations
Review

Leukemia inhibitory factor (LIF)

Nicos A Nicola et al. Cytokine Growth Factor Rev. 2015 Oct.

Abstract

Leukemia inhibitory factor (LIF) is the most pleiotropic member of the interleukin-6 family of cytokines. It utilises a receptor that consists of the LIF receptor β and gp130 and this receptor complex is also used by ciliary neurotrophic growth factor (CNTF), oncostatin M, cardiotrophin1 (CT1) and cardiotrophin-like cytokine (CLC). Despite common signal transduction mechanisms (JAK/STAT, MAPK and PI3K) LIF can have paradoxically opposite effects in different cell types including stimulating or inhibiting each of cell proliferation, differentiation and survival. While LIF can act on a wide range of cell types, LIF knockout mice have revealed that many of these actions are not apparent during ordinary development and that they may be the result of induced LIF expression during tissue damage or injury. Nevertheless LIF does appear to have non-redundant actions in maternal receptivity to blastocyst implantation, placental formation and in the development of the nervous system. LIF has also found practical use in the maintenance of self-renewal and totipotency of embryonic stem cells and induced pluripotent stem cells.

Keywords: Embryonic stem cells; JAK/STAT/SOCS; LIF receptor; Leukemia inhibitory factor; Nerve and muscle; Pregnancy.

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Conflict of interest statement

Conflict of Interest: NAN is an inventor on patents relating to LIF

Figures

Fig. 1
Fig. 1. LIF signals through a heterodimeric receptor
Both chains of the LIF receptor (LIFRβ and gp130) are shared by other IL-6 family cytokines. LIF and OSM bind a gp130:LIFRβ heterodimer whilst CNTF, CT-1 and CLC bind to the same heterodimer with the help of a specific receptor alpha chain (CNTFα). IL-6 and IL-11 bind a receptor that consists of two gp130 chains and two specific alpha chains (IL-6Rα and IL-11Rα respectively). Unlike other cytokines represented here, two molecules of IL-6 or IL-11 are required to form the signalling-competent complex, resulting in a hexamer.
Fig. 2
Fig. 2. A model of LIF bound to its receptor
Upper panels: Three orthogonal views of LIF (green) bound to the gp130 (blue):LIFRβ (red) heterodimer. Left and right panels show orthogonal views of the complex as viewed parallel to the cell-membrane whereas the central panel is viewed looking down towards the cell-membrane. Similar representations of the signalling-competent IL-6:gp130:IL-6Rα hexamer structure are shown below. The LIF receptor consists of two cytokine-binding modules (CBMs) separated by an immunoglobulin-like (Ig-like) domain. Three Fibronectin domains (FnIII) make up the “legs” of both receptors. gp130 has a similar architecture to LIFRβ but lacks the first CBM. Note the absence of an alpha-receptor (beige) in the LIF system. The LIF:LIFRβ:gp130 model was constructed by overlaying the structure of the LIFRβ:LIF (PDB ID: 2Q7N) complex onto the gp130 molecule from the IL-6:gp130:IL-6Ra hexamer (PDB IDs: 3L5H, 1P9M) and modelling the “legs” of LIFRβ on gp130 (PDB ID: 3L5H).
Fig. 3
Fig. 3. LIF signalling
Extracellular LIF stimulates JAK/STAT, MAPK and PI(3)K signalling, forming a 1:1:1 ternary complex. Intracellularly, both chains of the LIF receptor (LIFRβ and gp130) are bound to JAK1, the tyrosine kinase that initiates the signalling cascade. JAK1 phosphorylates five tyrosines on each receptor chain, four of these are docking sites for the transcription factor STAT3 (allowing stimulation of the JAK/STAT signalling pathway) whilst the fifth is a docking site for SHP-2 (which stimulates the MAPK pathway) and SOCS3 (which negatively regulates both the JAK/STAT and MAPK pathways). LIF stimulates a mixture of differentiation, survival and renewal programs, the balance of which determines the cell’s fate. In embryonic stem (ES) cells, signalling is skewed towards survival and self-renewal.
Figure 4
Figure 4. LIF actions in reproduction
A. LIF produced by the endometrial glands (and possibly by the blastocyst) acts on the endometrial epithelium to make it receptive to blastocyst attachment and on the stroma to decidualise it ready for implantation and placenta development. LIF also acts on the inner cell mass of the blastocyst to maintain totipotency during diapause and on the trophectoderm to induce trophoblast invasion into the endometrium. B. LIF is important for the formation of the maternal decidua and balanced LIF activity is essential for formation of trophoblast giant cells as well as the correct architecture of the labyrinth layer in which maternal and fetal blood vessels come into contact.
Fig. 5
Fig. 5. LIF actions in bone remodelling
LIF acts on bone stromal cells to enhance differentiation into bone-forming osteoblasts and inhibits the production of osteoblast-inhibitory sclerostin by osteocytes. Osteoblasts produce the TNF-like cytokine RANKL that acts on receptors on macrophages to induce differentiation into multi-nucleate osteoclasts that resorb bone. These linked phenomema allow repair of damaged bone by first clearing the damaged bone and then inducing new bone formation.
Fig. 6
Fig. 6. LIF and the hypothalamus-pituitary-adrenal axis
LIF acts on the anterior pituitary to enhance differentiation of precursors into corticotrophs rather than other cell fates and stimulates secretion of ACTH from corticotrophs synergistically with the cotricotropin-releasing hormone (CRH) produced by hypothalamic neurons. ACTH then acts on the adrenal cortex to secrete cortisol that has many effector actions in the stress response and also feeds back to inhibit the hypothalamic circuits and the anterior pituitary.
Fig. 7
Fig. 7. Neuromuscular effects of LIF
A. LIF acts on neural stem cells to increase self-renewal and can also act to stimulate the production and survival of neurons, GFAP+ astrocytes and oligodendrocytes that sheath neural axons (glial cells). It also acts to switch neurotransmitter choice of sensory neurons (from noradrenalin to acetylcholine). B. LIF is produced by skeletal muscle under load or after damage and stimulates proliferation of satellite cells while inhibiting their fusion into myotubes. Increased LIF production in damaged muscle or in neurons can be retrograde transported along axons to the nerve body (shown for motor neurons in the dorsal root ganglion) leading to increased survival.
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