Specific binding of leukemia inhibitory factor to murine myoblasts in culture

Bower, J.; Vakakis, N.; Nicola, Nicos A.; Austin, L.

doi:10.1002/jcp.1041640112

Cited by 36 publications

(20 citation statements)

References 17 publications

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“…In pituitary cells, protein-tyrosine phosphatases SHP1 and SHP2, and SOCS3, are proposed to down-regulate LIF signaling within 30 min to 1 h by inactivation of JAK2 and/or STAT3 (18 -21, 33). In myoblasts, it is also suggested that a separate mechanism operates via down-regulation of the LIFR␣ protein (9). To test the latter possibility, we measured the level of immunodetectable LIFR␣ after LIF treatment in the rat hepatoma cell line H-35.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Stimulation of Leukemia Inhibitory Factor Receptor Degradation by Extracellular Signal-regulated Kinase

Blanchard¹,

Duplomb²,

Wang³

et al. 2000

Journal of Biological Chemistry

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Leukemia inhibitory factor (LIF) signals via the heterodimeric receptor complex comprising the LIF receptor ␣ subunit (LIFR␣) and the common signal transducing subunit for interleukin-6 cytokine receptors, gp130. This study demonstrates that in different cell types, the level of LIFR␣ decreases during treatment with LIF or the closely related cytokine oncostatin M (OSM). Moreover, insulin and epidermal growth factor induce a similar LIFR␣ down-regulation. The regulated loss of LIFR␣ is specific since neither gp130 nor OSM receptor ␤ shows a comparable change in turnover. LIFR␣ downregulation correlates with reduced cell responsiveness to LIF. Using protein kinase inhibitors and point mutations in LIFR␣, we demonstrate that LIFR␣ downregulation depends on activation of extracellular signalregulated kinase 1/2 and phosphorylation of the cytoplasmic domain of LIFR␣ at serine 185. This modification appears to promote the endosomal/lysosomal pathway of the LIFR␣. These results suggest that extracellular signal-regulated kinase-activating factors like OSM and growth factors have the potential to lower specifically LIF responsiveness in vivo by regulating LIFR␣ half-life. Leukemia inhibitory factor (LIF)1 is one member of the interleukin (IL)-6-type family of cytokines that also include IL-6, IL-11, oncostatin M (OSM), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1), and neurotrophin-1. LIF is a pleiotropic cytokine that, among other functions, induces differentiation of mouse monocytic leukemia M1 cells, conversion of sympathetic neurons from the adrenergic to cholinergic phenotype, suppresses the differentiation of embryonic stem cells, enhances proliferation of myoblasts, and facilitates endometrial implantation of embryos (reviewed in Refs. 1 and 2).LIF also plays a role in the systemic inflammatory response, activating the hypothalamic-adrenal axis, and inducing the acute phase reaction of the liver (3). In hepatocytes, LIF, similar to other IL-6 cytokines, stimulates the enhanced expression of a set of plasma proteins, termed acute phase proteins (APP) (4). The precise pattern of APP expression is determined by the action of IL-6 cytokines in combination with various other inflammatory mediators, endocrine hormones, and growth factors (5). For instance, during the acute phase reaction, insulin is increased 3-fold (6) and then modulates the cytokine regulation of APP genes (7,8). In myoblasts, IGF-1 also reduces LIF action, apparently by down-regulating LIF receptor number (9).LIFR␣ is a 190-kDa transmembrane protein with low affinity for LIF. In combination with gp130 subunit, it forms the high affinity LIF receptor complex (10, 11). As described in the human system, OSM also uses LIFR␣ and gp130 subunits to form a high affinity OSM receptor complex (then termed OSMR complex type I). CNTF, CT-1, and neurotrophin-1 also utilize LIFR␣ and gp130 subunits (reviewed in Refs. 12 and 13). In addition to the shared LIFR␣/gp130 complex used by either LIF or OSM, a specific OSM receptor complex (type II) has bee...

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Section: Resultsmentioning

confidence: 99%

“…For instance, during the acute phase reaction, insulin is increased 3-fold (6) and then modulates the cytokine regulation of APP genes (7,8). In myoblasts, IGF-1 also reduces LIF action, apparently by down-regulating LIF receptor number (9).…”

mentioning

confidence: 99%

Stimulation of Leukemia Inhibitory Factor Receptor Degradation by Extracellular Signal-regulated Kinase

Blanchard¹,

Duplomb²,

Wang³

et al. 2000

Journal of Biological Chemistry

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“…However, both mRNAs were apparently downregulated in the newly formed myotubes. There are many data showing that LIF is upregulated in regenerating myofibers and that this contributes to the proliferation of myoblasts in vitro (Austin et al 1992;Barnard et al 1994;Bower et al 1995;Kami and Senba 1998). The complex of gp130 and LIFR is also utilized as a signal transducer to mediate the biological actions of CNTF, OM, and CT-1 (Kishimoto et al 1994), but there are no reports suggesting the synthesis of these cytokines in regenerating muscles or their roles in myogenesis in vivo or in vitro.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression of Receptors for IL-6, LIF, and CNTF in Regenerating Skeletal Muscles

Kami

Morikawa²,

Sekimoto³

et al. 2000

J Histochem Cytochem.

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The biological actions of interleukin-6 (IL-6), leukemia inhibitory factor (LIF), and ciliary neurotrophic factor (CNTF) are mediated via respective functional receptor complexes consisting of a common signal-transducing component, gp130, and other specific receptor components, IL-6 receptor α (IL-6R), LIF receptor β (LIFR), and CNTF receptor α (CNTFR). IL-6, LIF, and CNTF are implicated in skeletal muscle regeneration. However, the cell populations that express these receptor components in regenerating muscles are unknown. Using in situ hybridization histochemistry, we examined spatiotemporal expression patterns of gp130, IL-6R, LIFR, and CNTFR mRNAs in regenerating muscles after muscle contusion. At the early stages of regeneration (from 3 hr to Day 2 post contusion), significant signals for gp130 and LIFR mRNAs were detected in myonuclei and/or nuclei of muscle precursor cells (mpcs) and in mononuclear cells located in extracellular spaces between myofibers after muscle contusion, but IL-6R mRNA was expressed only in mononuclear cells. At Day 7 post contusion, signals for gp130, LIFR, and IL-6R mRNAs were not detected in newly formed myotubes, whereas the CNTFR mRNA level was upregulated in myotubes. These findings suggest that the upregulation of receptor subunits in distinct cell populations plays an important role in the effective regeneration of both myofibers and motor neurons.

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“…Because the density of high-affinity receptors on LIF-responsive cells is relatively low, with an average of 300 binding sites per cell (Godard et al, 1992;Tomida, 2000), LIF binding is a low-capacity process that may readily become saturated. Following receptor binding, the entire LIF-receptor complex is subject to internalization and degradation by lysosomal enzymes (Bower et al, 1995).…”

Section: Methodsmentioning

confidence: 99%

“…The collective processes of internalization, intracellular transport, and lysosomal degradation are characterized by a first-order rate constant, k int . Because in vitro studies have demonstrated that the LIF receptor is degraded within the cell, a receptor recycling component is not required in this model (Bower et al, 1995).…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics of Recombinant Human Leukemia Inhibitory Factor in Sheep

Segrave

Mager

Charman

et al. 2004

J Pharmacol Exp Ther

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The pharmacokinetics of recombinant human leukemia inhibitory factor (rhLIF) were investigated following i.v. and s.c. administration of a wide range of dose levels. Parallel studies were conducted where single i.v. bolus doses of 12.5, 25, 100, 250, 500, or 750 g/kg rhLIF (n ϭ 2) or s.c. doses of 10, 20, or 50 g/kg rhLIF (n ϭ 4) were administered to sheep. Blood samples were collected for up to 24 h postdosing, and the plasma concentrations of rhLIF were analyzed by enzyme-linked immunosorbent assay. Noncompartmental analysis demonstrated an increase in the terminal elimination half-life (from 0.27 to 2.29 h) and a decrease in systemic clearance (from 5.18 to 1.09 ml/min/kg) with increasing i.v. doses of rhLIF, suggesting nonlinear pharmacokinetic behavior. A greater than proportional increase in the area under the plasma concentration-time curve with dose also indicated significantly nonlinear pharmacokinetics after s.c. administration. A mechanistic compartmental model was developed to characterize the pharmacokinetics of rhLIF. The key feature of the model accounting for the nonlinear pharmacokinetic behavior of rhLIF was high-affinity, saturable receptor binding and subsequent cellular internalization and degradation. The apparent total density of LIF cell surface receptors and receptor turnover dynamics were included in the model, along with nonspecific binding and linear elimination from the systemic circulation. The absorption of rhLIF from the s.c. injection site into the systemic circulation was characterized by a first-order absorption process via a delay compartment. The proposed model satisfactorily captured the complex pharmacokinetic profiles of rhLIF following both i.v. and s.c. administration.

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Specific binding of leukemia inhibitory factor to murine myoblasts in culture

Cited by 36 publications

References 17 publications

Stimulation of Leukemia Inhibitory Factor Receptor Degradation by Extracellular Signal-regulated Kinase

Stimulation of Leukemia Inhibitory Factor Receptor Degradation by Extracellular Signal-regulated Kinase

Gene Expression of Receptors for IL-6, LIF, and CNTF in Regenerating Skeletal Muscles

Pharmacokinetics of Recombinant Human Leukemia Inhibitory Factor in Sheep

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