Leukemia inhibitory factor as an intrapituitary regulator of pro-opiomelanocortin gene expression and corticotrope ontogeny.

Along with the well characterized control of pituitary function by hypothalamic hormones, several cytokines mediate signaling between the neuroendocrine and immune systems. Interleukin-1 (IL-1), IL-6, tumor necrosis factor-a and, recently, leukemia inhibitory factor (LIF) and IL-11 (1, 2) are the most thoroughly characterized. LIF belongs to the IL-6 cytokine family, together with IL-6, IL-11, oncostatin M, cilary neurotropic factor and cardiotropin-1. LIF was originally characterized and so named for its ability to promote the differentiation of a mouse myeloid leukemic cell line (3). LIF is a pleiotropic cytokine and has diverse biological activities, including regulation of hematopoietic cell proliferation and differentiation, stimulation of neuronal growth and development, bone formation, and preparation of the uterus for embryo implantation. Melmed and his colleagues have shown that LIF participates in regulating gene expression of pro-opiomelanocortin (POMC), in addition to corticotropin-releasing hormone (CRH) and glucocorticoids (4–6). LIF gene expression has been demonstrated in human fetal and adult pituitary cells (4), murine corticotrope tumor AtT20 cells (5), and murine hypothalamus and pituitary (7), where it was constitutively expressed and induced in response to lipopolysaccharide endotoxin (7) and IL-1b (2). In AtT20 cells, LIF induces POMC promoter activity, POMC mRNA expression, and adrenocorticotropin (ACTH) secretion. CRH acts synergistically with LIF to stimulate POMC gene expression, whereas glucocorticoids blunt LIF-induced ACTH secretion (4–6). LIF induces ACTH secretion in vitro in primary cultured rat (8) and sheep (9) pituitary cells, and in vivo in fetal monkeys (10) and in mice (7). LIF null mice exhibit an attenuated hypothalamo-pituitary-adrenal (HPA) axis response to stress, especially to chronic inflammatory stress (7) and IL-1 (2), which is restored by delivery of LIF. However, the basal corticosterone plasma level and the response to psychological stress appear intact. In vitro, LIF induces a switch in proliferating corticotrope tumor AtT20 cells towards a more differentiated phenotype (11). In vivo, transgenic mice expressing LIF driven by the rat growth hormone promoter exhibit persistent Rathke’s cysts and somatotrope deficiency (11). LIF transgenic mice expressing LIF driven by the pituitary glycoprotein hormone a-subunit promoter (6) exhibit mild morphological and biochemical features of hypercorticosteronism consistent with Cushing’s syndrome associated with corticotrope hyperplasia, deficiency of the other pituitary lineages and multiple Rathke-like cysts. Inhibitory effects on the other axis may, in part, be secondary to LIF-induced hypercorticosteronism. It was suggested that LIF could divert progenitor cells to differentiate from Lhx3-dependent cell lineages (gonadotrope, thyrotrope, somatotrope and lactotrope) to an Lhx3-independent cell lineage (corticotrope), as indicated by the marked reduction in Lhx3 and Pit1 expression, and favor differentiation into ciliated cells. These findings suggest that, together with specific transcription factors, LIF may participate in pituitary ontogeny. In a wide variety of cells, LIF binding is associated with gp130 (a transmembrane protein subunit shared by the members of the IL-6 cytokine family) and LIF receptor subunit heterodimerization. Subsequent to LIF receptor dimerization, Janus kinase (JAK) is activated by tyrosine trans/autophosphorylation which leads to tyrosine phosphorylation, homoor heterodimerization and nuclear translocation of Stat3 and Stat1 (signal transducers and activators of transcription). Although LIF action occurs mainly through the JAK/Stat pathway, other subcellular signaling pathways are activated by IL-6-related cytokines including the Ras-MAPK pathway, phospholipase C, phosphoinositol 3-kinase, phosphotyrosine phosphatase D, pp120 and insulin receptor substrate-1 (12). To explore molecular mechanisms of LIF action, AtT20 transformants for mutated Stat3 were developed. These mutants act in a dominant negative manner by blocking endogenous Stat3 tyrosine phosphorylation or Stat3 DNA binding, and cause attenuation of LIF-induced transcriptional activation of the POMC promoter, POMC mRNA levels and ACTH secretion. These results indicate a requirement for Stat3 in mediating LIF induction of POMC expression. Furthermore, LIF induces a negative feedback loop in AtT20 cells and in murine pituitary through SOCS-3 (suppressor of cytokine signaling-3), European Journal of Endocrinology (1999) 141 214–215 ISSN 0804-4643