Functions of LIF

Hematopoietic cells

LIF was identified as a factor capable of inducing the terminal differentiation of the murine myeloid leukemic cell line Ml into macrophages. Activation of the transcription factor STAT3 is essential for LIF-induced differentiation of Ml cells. A number of myeloid leukemic cell lines, which were unresponsive to treatment with LIF, expressed various defects in the JAK/STAT signal cascade, suggesting modulations of this pathway to be a crucial step in leukemo-genesis. Although LIF expressed pronounced effects on leukemic cells it had no proliferative activity on normal hematopoietic progenitor cells. Mice with targeted disruption of the LIF receptor ligand-bind-ing chain contained a normal hematologic cell compartment. Targeted disruption of the gp!30 signal transducer chain led to hematological disorders during embryogenesis, demonstrating a crucial involvement of gpl30-mediated signaling. Attempts to maintain or expand primitive hematopoietic stem cells in vitro without concomitant loss of their differ-entiative and proliferative potential in vivo were significantly more successful by culturing the cells in the presence of LIF. The effect of LIF on long-term re-populating stem cells resulted from promoting cytokine expression by bone marrow stroma and may thus be an important tool in blood cell transplantation and transfusion medicine.

Acute phase response

The acute phase response is a systemic reaction against infection or tissue injury, which involves fever, leukocytosis, increased vascular permeability and increased serum levels of acute phase proteins. Acute phase proteins are synthesized in the liver in response to increased levels of certain cytokines including IL-1, TNFa and IL-6. LIF can induce the same set of acute phase proteins as IL-6. This is due to the use of the same signal cascade leading to activation of transcription factors of the STAT family, which then bind to specific control regions of various acute phase genes. In addition, LIF stimulates hepatic triglyceride secretion and mediates changes in lipid metabolism that accompany the acute phase response.

The involvement of LIF in postoperative anorexia and in cancer cachexia is likely to be mediated centrally by decreased food uptake and in addition by-its influence on lipid metabolism, both leading to loss of body weight.

LIF is a cytokine released at the site of local injuries, where a recruitment of monocytes and polymorphonuclear cells takes place. Supernatants of monocytes treated with LIF had chemotactic activity for neutrophils and monocytes. LIF acts as an endogenous mediator of cutaneous inflammation and is a mediator of (CMV)-induced inflammatory reactions.

Nervous system

LIF/CNTF has been known to switch the pattern of neurotransmitter expression from the noradrenergic to the cholineric phenotype. Like CNTF, LIF has profound effects on the survival and maintenance of motor neurons. In addition, LIF may be important during cerebral infection and inflammation. Primary astrocyte cultures express LIF mRNA constitutively, and this expression is regulated by proinflammatory and anti-inflammatory stimuli, suggesting that astrocytes may be an important source of LIF during cerebral inflammation and infection. A rapid upregul-ation of LIF in the nerve segments, produced by Schwann cells subsequent to nerve injuries, leads to the suggestion that LIF acts as a trauma factor in injured peripheral nerves.

Development

LIF is expressed in a menstrual cycle-dependent manner in human endometrium, with maximal values coinciding with the time of implantation. LIF induces the expression of other cytokines to regulate the temporal and spatial production and activity of proteases and protease inhibitors to create a favorable environment for implantation. By increasing the synthesis of fibronectin LIF acts on human trophoblasts and shifts their differentiation towards the anchoring phenotype.

LIF and cancer

A variety of cancer cells have been shown to respond to LIF by stimulation of proliferation using either a paracrine or an autocrine mechanism. In addition, LIF modulates the capacity of tumor cells to adhere to matrix components, a requisite for a metastatic process, suggesting a potential role in the modulation of tumor progression. The levels of soluble LIF produced by various tumor cell clones correlated with their tumorigenicity.

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