The LIF cytokine: towards adulthood

Abstract

The aim of this article is to recapitulate the key features of leukaemia inhibitory factor cytokine (LIF), to review its numerous physiological effects and to comment on the most recent data. We will also present results of transcriptome analyses, which have highlighted different categories of LIF targets, identified in murine embryonic stem (ES) cells and early derivatives. We hope to stimulate new research fields on this puzzling cytokine, which, forty years after its discovery, has still not disclosed all its secrets.

LIF-Dependent Signaling: New Pieces in the Lego

“…Three laboratories simultaneously discovered and cloned the LIF cytokine through its pleiotropic biological activities on i) the proliferation of adult human T cells (HILDA; [3]), ii) the maintenance of ES cells pluripotency (DIF [4]) and iii) the inhibition of leukemic cell differentiation (LIF; [5]). LIF was thus characterized as a pleiotropic cytokine with pro or anti-differentiation, pro or anti-survival effects depending upon cell maturity and cell types [6, 7]. …”

“…Studies of LIF Knock-Out (KO) mice revealed that LIF is essential for the implantation process of blastocysts, for the maintenance of hematopoietic stem cell pools and for the not so well understood mechanisms leading to cachectic animals ([18–20] and reviewed in [7]). In addition, in LIF rescued KO mice model, it was shown that LIF is essential for mammary gland involution after lactation [21].…”

“…We propose to view LIF signaling as a Lego built with different combinations of similar pieces, leading to various outcomes, which range from cell proliferation and survival to differentiation and apoptosis, depending on maturity and cell types [1, 2, 7, 42]. This Lego includes the “ptyr signaling toolkit” described recently by Lim and Pawson [43].…”

“…Eed protein, a LIF-dependent STAT3 target of the repressive Polycomb complex, has been shown to silence differentiation-associated genes in self-renewing mES cells [49]. We have proposed that the level of expression and/or of activation of chromatin regulators could end up to opened or closed chromatin configuration, leading to accessibility (or not) of STAT3-dependent promoters, helping to explain opposite outcomes of LIF/STAT3 pathway [7]. It might be informative to perform parallel Chromatin Immunoprecipitation (ChIP)-seq analyses with anti-phosphoSTAT3 antibody in mES and in the M1 cell line (a leukemic myeloid cell line in which LIF triggers differentiation) to characterize LIF/STAT3—dependent promoters in two cell models in which LIF drives opposite effects [50–54].…”

Bilateral Giant Retinal Tears in a Pediatric Patient With Leukemia Inhibitory Factor Receptor Deficiency (Stuve-Wiedemann Syndrome)

“…1 The molecular defect has been identified as inactivating mutations in the gene encoding for the gp190 subunit of the leukemia inhibitory factor receptor (LIFR). 2 Most patients do not survive past infancy, with the most common cause of death being sepsis. 3 Ocular manifestations have included severe neurotrophic corneal changes including opacity, neovascularization, thinning, and ocular perforation.…”