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PubMed1995

Interleukin-6-type cytokines and their receptors for gene therapy of melanoma.

B-78-H1 melanoma cells were stably transfected with cDNAs encoding human IL-6, human LIF, murine sIL-6R and murine sLIFR. The mock transfected and transfected cells demonstrated no detectable H-2Kb molecules. B-78 transfected cells were subcutaneously (s.c.) and intravenously (i.v.) injected to B57BL/6 x C3H mice. Control B-78 cells formed tumors and lung metastases in injected animals. Cells transfected with IL-6, LIF and sIL-6R showed greatly reduced tumor and metastases formation. Transfection of IL-6, sIL-6R or LIF had similar protective effects while the combination of IL-6 and sIL-6R was most effective. In contrast, cells transfected with sLIFR showed reduced metastasis formation but increased tumor growth compared to mock transfected cells. Kinetic analysis demonstrated a 3 weeks lag period between the formation of tumors by B-78 cells and the combination of B-78 cells transfected with IL-6 and sIL-6R. No such lag phase was seen when B-78-IL-6 or B-78-sIL-6R cells were injected alone. Mice primarily injected s.c. with a mixture of IL-6 and sIL-6R transfected cells and rechallenged after 2 weeks with parental B-78 cells demonstrated long-lasting antitumor immunity. IL-6 and sIL-6 transfected cells used alone for immunization had only limited effect. Injection of transfected cells into SCID mice which are characterized by greatly reduced number of T and B cells, showed a protective effect of sIL-6R on metastasis formation by B-78 cells. beta 2m knockout mice lacking CD8+ T cells, injected with B-78 cells developed tumors and died after 2 weeks. However, B-78 cells transfected with IL-6 developed tumors in only 50% of animals. Mice without tumors rechallenged with B-78 cells demonstrated required immunity against parental melanoma cells. The results obtained indicate that studied IL-6-type cytokines and their respective soluble receptors affect murine melanoma growth and metastasis formation. The major finding of these studies is that IL-6 complexed with sIL-6R demonstrated qualitatively different biological activity than IL-6 alone especially in stimulating long lasting anti-melanoma immunity. The proposed mechanism of action of such complexes beside activation of cytotoxic T lymphocytes is activation of NK cells.

Animals↗
PubMed1992

The IL-6 signal transducer, gp130: an oncostatin M receptor and affinity converter for the LIF receptor.

Leukemia inhibitory factor (LIF) and interleukin-6 (IL-6) are multifunctional cytokines with many similar activities. LIF is structurally and functionally related to another cytokine, Oncostatin M (OSM), that binds to the high-affinity LIF receptor but not to the low-affinity LIF receptor. A complementary DNA was isolated that encodes the high-affinity converting subunit of the LIF receptor. The converter conferred high-affinity binding of both LIF and OSM when expressed with the low-affinity LIF receptor and is identical to the signal transducing subunit of the IL-6 receptor, gp130. The gp130 subunit alone confers low-affinity binding of OSM when expressed in COS-7 cells. This receptor system resembles the high-affinity receptors for granulocyte-macrophage colony-stimulating factor, IL-3, and IL-5, which share a common subunit.

Animals↗
PubMed1995

Designer cytokines: targeting actions to cells of choice.

Some growth factors are therapeutically useful partly because restricted expression of their receptors limits their action to particular cell types. However, no unique stimulatory factor is known for many clinically relevant cell types, such as CD34+ hematopoietic stem cells. Here, soluble alpha receptor (R alpha) components for interleukin-6 (IL-6) and ciliary neurotrophic factor (CNTF) were targeted in an active form to cells expressing surface markers such as CD34 or CD45, thereby rendering those cells responsive to IL-6 or CNTF. The targeting of R alpha components may provide the means to create "designer" cytokines that activate a desired cell type expressing a specific cell surface marker.

Animals↗
PubMed1995

Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors.

Many members of the cytokine receptor superfamily initiate intracellular signaling by activating members of the Jak family of tyrosine kinases. Activation of the same Jaks by multiple cytokines raises the question of how these cytokines activate distinct intracellular signaling pathways. Selection of particular substrates--the transcriptional activator Stat3 and protein tyrosine phosphatase PTP1D--that characterize responses to the ciliary neurotrophic factor-interleukin-6 cytokine family depended not on which Jak was activated, but was instead determined by specific tyrosine-based motifs in the receptor components--gp130 and LIFR--shared by these cytokines. Further, these tyrosine-based motifs were modular, because addition of a Stat3-specifying motif to another cytokine receptor, that for erythropoietin, caused it to activate Stat3 in a ligand-dependent fashion.

Amino Acid Sequence↗
PubMed1994

Role of leukemia inhibitory factor and its receptor in mouse primordial germ cell growth.

The pleiotropic cytokine leukemia inhibitory factor (LIF) is able to promote the growth of mouse primordial germ cells (PGCs) in culture. It is unclear whether LIF acts directly on PGCs or indirectly via feeder cells or embryonic somatic cells. To understand the role of LIF in PGC growth, we have carried out molecular and cell culture analyses to investigate the role of both the LIF ligand and its receptor in PGC development. LIF is able to stimulate PGC growth independently of the presence of feeder cells supporting the hypothesis that LIF acts directly on PGCs to promote their growth. We show here that transcripts for the low-affinity LIF receptor (LIFR), an integral component of the functional LIF receptor complex, are expressed in the developing gonad. Fluorescence-activated cell sorter (FACS) analysis, using an anti-LIFR antiserum, demonstrates that LIFR is present on the surface of PGCs, suggesting that PGCs are likely to be a direct target of LIF action in culture. Signalling via LIFR is essential for PGC growth in culture since the anti-LIFR antiserum, which blocks LIF binding to its receptor, abolishes PGC survival in culture. Two LIF-related cytokines, namely oncostatin M and ciliary neurotrophic factor, can also promote PGC growth in culture in addition to LIF. Thus one or more of these LIFR-dependent cytokines may play an important role in PGC development in mice.

Animals↗
PubMed1995

Targeted disruption of the low-affinity leukemia inhibitory factor receptor gene causes placental, skeletal, neural and metabolic defects and results in perinatal death.

The low-affinity receptor for leukemia inhibitory factor (LIFR) interacts with gp130 to induce an intracellular signal cascade. The LIFR-gp130 heterodimer is implicated in the function of diverse systems. Normal placentation is disrupted in LIFR mutant animals, which leads to poor intrauterine nutrition but allows fetuses to continue to term. Fetal bone volume is reduced greater than three-fold and the number of osteoclasts is increased six-fold, resulting in severe osteopenia of perinatal bone. Astrocyte numbers are reduced in the spinal cord and brain stem. Late gestation fetal livers contain relatively high stores of glycogen, indicating a metabolic disorder. Hematologic and primordial germ cell compartments appear normal. Pleiotropic defects in the mutant animals preclude survival beyond the day of birth.

Animals↗
PubMed1995

Expression patterns of leukaemia inhibitory factor receptor (LIFR) and the gp130 receptor component in rabbit uterus during early pregnancy.

The presence of leukaemia inhibitory factor (LIF) binding and expression of the gp130 component of the LIF receptor were studied in the rabbit uterus during pregnancy. LIF binding to myometrium was moderate in oestrous and non-oestrous animals and on day 1 of pregnancy, declined on days 2 and 3, and increased to a peak value on days 5 and 6 of pregnancy. Binding to stromal cells was not observed. Binding of LIF to luminal and glandular epithelium was low in unmated animals and on days 1 and 2 of pregnancy. Binding to luminal epithelium increased from day 3, and to glandular epithelium from day 5 of pregnancy. Highest binding was seen on days 5 and 6, with a slight decline observed on day 7, and with little difference between the mesometrial and antimesometrial regions of the implantation site. In all cases, binding of LIF was similar in the uteri of day 6 pseudopregnant and pregnant animals. At all stages, gp130 was absent from stroma and almost absent from myometrium and glandular epithelium. It was expressed in luminal epithelium, reaching maximal expression on day 6 of pregnancy and pseudopregnancy, but diminished on day 7 of pregnancy, particularly in the antimesometrial area of the implantation site. The coexpression of LIF binding and gp130 may indicate the presence of high-affinity LIF receptor, which matches the pattern of LIF protein expression and, as in mice, suggests its importance for implantation.

Animals↗
PubMed1992

Inhibition of differentiation in a murine F9 embryonal carcinoma cell subline by leukemia inhibitory factor (LIF).

Leukemia inhibitory factor (LIF) is a cytokine previously shown to maintain pluripotent embryonic stem cells in their undifferentiated state. We have examined the effects of LIF in nullipotent embryonal carcinoma cell lines, and have found that LIF blocks differentiation induced by retinoic acid and at low temperature in OTF9 cells. LIF did not block differentiation in a parent F9 cell line. For OTF9 cells, LIF acts early in differentiation, inhibiting the appearance of parietal endoderm-type product cells. However, it acts subsequent to retinoic acid, and at least one early retinoic acid-induced event is unaltered in the presence of LIF. This finding provides both a means of dissecting the cascade of events leading to EC cell differentiation, and a well-characterised target cell type for studying the mechanism of action of LIF.

Animals↗
PubMed1992

Leukemia inhibitory factor--a puzzling polyfunctional regulator.

LIF seems likely to have important functions in the early developing embryo and in adult life can influence platelet formation, osteoblast and neuronal function, calcium and lipid metabolism and the production of acute-phase proteins. LIF appears usually to be produced and to function locally in various tissues, an arrangement that would minimize unwanted actions of this polyfunctional regulator. Nevertheless it remains puzzling what purpose is achieved by use of a regulator with potent actions on such a wide range of apparently unrelated tissues.

Animals↗
PubMed1992

Oncostatin M is a differentiation factor for myeloid leukemia cells.

Oncostatin M (OSM) is a 28-kDa glycoprotein produced by stimulated macrophages and T lymphocytes that inhibits the proliferation of a number of different cell lines derived from solid tumors. Analysis of both amino acid sequence and gene structure has demonstrated that OSM is a member of a cytokine family that includes leukemia inhibitory factor (LIF), IL-6, and granulocyte colony-stimulating factor (G-CSF). We demonstrate that, like LIF, IL-6 and G-CSF, OSM can induce the differentiation of the myeloblastic M1 murine leukemia cells into macrophage-like cells. The morphologic and functional changes induced by OSM are more similar to those observed with LIF and IL-6 than those induced with G-CSF. OSM can also induce the differentiation of the histiocytic U937 human leukemia cells in the presence of granulocyte-macrophage CSF, a property shared with LIF and IL-6. In murine M1 cells, binding of labeled OSM is completely inhibited by excess LIF or OSM, reflecting the binding of OSM to the high affinity form of the murine LIF receptor. In contrast, the binding of labeled OSM to human U937 leukemia cells is inhibited by OSM, but the inhibition by LIF is significantly less. These results suggest that, in human leukemia cells, OSM may act through the LIF receptor and an OSM-specific receptor. The existence of an OSM-specific receptor was confirmed by both growth inhibition and competition binding assays on A375 human melanoma cells. The growth of human A375 cells was inhibited by OSM and IL-6 but not LIF or G-CSF. Neither LIF, G-CSF, nor IL-6 could compete with the binding of labeled OSM to A375 cells.

Animals↗
PubMed1992

Down-regulation of interleukin 6 receptors of mouse myelomonocytic leukemic cells by leukemia inhibitory factor.

We examined the effect of leukemia inhibitory factor (LIF) on the expression of interleukin 6 receptors (IL-6R) on mouse myelomonocytic leukemic M1 cells. Binding studies using 125I-labeled human and murine IL-6 revealed that LIF caused a decrease in IL-6 binding to M1 cells. The decrease became evident within 1 h, and the maximum decrease was observed at 3-6 h. Scatchard plot analysis revealed that M1 cells had a single class of high affinity receptors for IL-6 and that LIF-induced decrease in IL-6 binding was due to a decrease in the number of IL-6R on the cell surface and not to changes in their affinity. The affinity of IL-6R on M1 cells to human IL-6 (Kd = 2.25 nM) was about 10-fold lower than that to murine IL-6 (Kd = 200 pM). The amount of IL-6 secreted into culture media by M1 cells that were treated with LIF for up to 12 h was not enough to cause receptor down-regulation. Northern blot analysis demonstrated that IL-6R mRNA was down-regulated by LIF treatment, and similar regulation was also observed when the cells were treated with IL-6. The time course of the IL-6R mRNA level was similar to that of IL-6R expression on the cell surface, suggesting that the main mechanism responsible for the loss of high affinity IL-6R was the regulation of IL-6R mRNA. Although the half-life of IL-6R on the cell surface was about 30 min, the addition of LIF reduced it to 16 min, suggesting the existence of an additional mechanism responsible for the loss of high affinity IL-6R on the cell surface.

Animals↗
PubMed1992

[Function, molecular structure and gene expression regulation of receptor for D-factor/LIF].

Differentiation-stimulating factor (D-factor)/leukemia inhibitory factor (LIF) is a cytokine inducing differentiation of mouse myeloid leukemic M1 cells. IL-6, oncostatin M (OSM) and G-CSF also induce differentiation of M1 cells. These four cytokines are suggested to be members of a single cytokine family. The LIF receptor is structurally related to the gp130 signal-transducing component of the IL-6 receptor and to the G-CSF receptor. The high-affinity receptors for LIF, OSM and IL-6 share the common subunit, gp130. This provides an explanation for the functional redundancy of those cytokines.

Animals↗
PubMed1992

Oncostatin M binds the high-affinity leukemia inhibitory factor receptor.

Oncostatin M (OSM) is a glycoprotein cytokine that was recently demonstrated to be structurally and functionally related to the leukemia inhibitory factor (LIF). We have investigated the binding of each cytokine to a variety of cellular receptors including those on solid tumor lines, leukemic cells, endothelial cells, macrophages, and cells transfected with the recently cloned low-affinity LIF receptor, and to a soluble form of the LIF receptor. LIF is incapable of binding either high- or low-affinity OSM receptors, yet OSM is capable of binding the high-affinity but not the low-affinity LIF receptor. Since the presence of high-affinity LIF receptors correlates with the biological activity of LIF on a wide range of target cells, we predict that OSM should have similar effects on LIF-responsive cells.

Animals↗
PubMed1992

Kinetic analyses of the binding of leukemia inhibitory factor to receptor on cells and membranes and in detergent solution.

The equilibrium and kinetic properties of leukemia inhibitory factor (LIF) binding to a range of cell types have been compared. When binding was examined at 4 degrees C, the majority of cells were found to express a single class of high affinity LIF receptor (KD = 20-100 pM; ka = 2-8 x 10(8) min-1 M-1; kd = 0.0004-0.0011 min-1). In contrast, certain activated macrophage populations expressed apparently independent classes of high and low affinity LIF receptor. The low affinity receptors differed from the high affinity receptors in terms of the dissociation rate of the receptor-ligand complex (KD = 1-2 nM; ka = 3-7 x 10(8) min-1 M-1; kd = 0.30-0.67 min-1). At 37 degrees C, the interaction of LIF with its high affinity receptor was more complicated, since occupied LIF receptors were internalized more rapidly than unoccupied receptors, internalized LIF was hydrolyzed and released from the cell, and new receptors were synthesized and expressed on the cell surface. Interestingly, when membranes were prepared from cells that expressed only high affinity receptors, both high and low affinity receptors were detected, while after detergent solubilization of membranes only low affinity receptors were apparent. These results are discussed in terms of a structural model for the LIF receptor in which interaction of a low affinity binding subunit and a second nonbinding subunit is required for the generation of the high affinity receptor.

3T3 Cells↗
PubMed1992

High and low affinity receptors for human interleukin for DA cells/leukemia inhibitory factor on human cells. Molecular characterization and cellular distribution.

Radioiodinated recombinant human interleukin DA (HILDA)/leukemia inhibitory factor (LIF) purified from conditioned medium of Chinese hamster ovary transfected cells enabled the identification of specific receptor sites on a variety of human cell types. Using low concentrations (up to 500 pM) of the ligand iodinated at a high specific radioactivity, high affinity receptors (equilibrium dissociation constant Kd in the range of 30-100 pM) were first demonstrated. They were expressed at low levels by human peripheral blood monocytes but not by lymphocytes, NK cells, granulocytes, and platelets. The myelomonocytic cell line THP1 as well as the T lymphoma cell line HSB2 and the lymphoblastoid B cell line DAB were also receptor-negative. In contrast, most of the non-lymphoid tumoral cell lines tested, including melanomas, neuroblastomas, and carcinomas, expressed high affinity HILDA/LIF receptors at variable levels (Bmax from 20 to 600 sites/cell). The kinetics of HILDA/LIF high affinity binding to the choriocarcinoma JAR cell line were characterized at 4 degrees C with association and dissociation rate constants of k1 = 2.2 10(9) M-1 min-1 and k-1 = 0.0084 min-1, respectively, corresponding to a steady-state dissociation constant k1/k-1 = 3.8 pM. The subsequent use of higher concentrations of HILDA/LIF labeled at a lower specific radioactivity enabled the identification of a low affinity component on several cell lines (Kd in the range of 1-4 nM; Bmax from 1,000 to 5,000 sites/cell). On JAR cells, this low affinity component was characterized by association and dissociation rate constants at 4 degrees C of k1 = 7.3 10(7) M-1 min-1 and k-1 = 0.19 min-1, respectively (k-1/k1 = 2.6 nM). Affinity cross-linking of HILDA/LIF to JAR cells showed two cross-linked species under both reducing and nonreducing conditions corresponding to receptor species of 120 and 250 kDa, respectively. Whereas both bands had similar intensities under high affinity conditions, the higher band predominated under low affinity conditions. Our data suggest that the 250-kDa chain could constitute the low affinity binding component whereas the association of both 250- and 120-Da subunits would form the high affinity structure.

Animals↗
PubMed1991

Leukemia inhibitory factor can potentiate murine megakaryocyte production in vitro.

Receptors for murine leukemia inhibitory factor (LIF) were demonstrated on immature and mature murine megakaryocytes. LIF alone had no effects in culture on the survival or proliferation of normal murine megakaryocytes or their precursors. However, combination of LIF with multipotential-colony-stimulating factor (Multi-CSF) (interleukin-3) enhanced the megakaryocyte colony formation able to be stimulated by Multi-CSF; the enhancement involved all types of megakaryocyte colony and resulted in the formation of increased numbers of megakaryocytes. These observations provide a possible basis for the observation that, when LIF is injected in vivo, elevations are observed in megakaryocyte numbers and platelet levels.

Animals↗