Gp130 and ras mediated signaling in human plasma cell line INA-6: a cytokine-regulated tumor model for plasmacytoma.

Introduction: Cytokines of the gp130-family, particularly interleukin(IL)-6, play a crucial role in the propagation of malignant plasma cells.

Materials And Methods: The role of IL-6 and other gp130-cytokines was studied in the human plasma cell line INA-6 in vitro and in INA-6 xenografts. The proliferative response to gp130-cytokines was evaluated and activated components of gp130-signaling pathways were identified by Western blotting and DNA binding studies.

Rab11b is essential for recycling of transferrin to the plasma membrane.

Members of the Rab family of small GTPases play important roles in membrane trafficking along the exocytic and endocytic pathways. The Rab11 subfamily consists of two highly conserved members, Rab11a and Rab11b. Rab11a has been localized both to the pericentriolar recycling endosome and to the trans-Golgi network and functions in recycling of transferrin.

Interleukin-6 activates signal transducer and activator of transcription and mitogen-activated protein kinase signal transduction pathways and induces de novo protein synthesis in human neuronal cells.

Interleukin-6 (IL-6) is involved in the pathophysiology of various diseases of the CNS. Because the molecular mechanism of action of this cytokine in human neurons is not well understood, we were interested in characterizing and defining a model system for IL-6-induced activation of signal transduction cascades, transcriptional activation, and protein synthesis in human neuronal cells. We show that IL-6 leads to transcriptional activation of signal transducer and activator of transcription 3 (STAT3) in human SH-SY5Y neuroblastoma cells.

Reconstitution of IL6-inducible differentiation of a myeloid leukemia cell line by activated Stat factors.

Differentiation of the myeloid leukemia cell line M1 by treatment with IL6-type cytokines depends on activation of the Jak/Stat (Janus kinase/signal transducer and activator of transcription) pathway. Defects in this cascade are correlated with an impaired cytokine-inducible differentiation of various other myeloid cell lines. Although treatment with IL-6 increased the amount of activated transcription factor Stat3 in the myeloid leukemia line C, differentiation was not induced.

Modulation of the activation status of Stat5a during LIF-induced differentiation of M1 myeloid leukemia cells.

Treatment of M1 myeloid leukemia cells with leukemia inhibitory factor (LIF) causes activation of transcription factors Stat1, Stat3 and Stat5a (signal transducers and activators of transcription). DNA-binding of Stat proteins was detectable for extended periods of time in LIF-treated M1 cells, which simultaneously underwent terminal differentiation. The relative composition of Stat factors in the protein-DNA complexes changed during time.

Transcription factor Stat5 is an early marker of differentiation of murine embryonic stem cells.

Embryonic stem (ES) cells are pluripotent descendants of the inner cell mass of blastocysts capable of differentiating into progenitor cells of most if not all tissues. The pluripotency of ES cells is maintained by leukemia inhibitory factor (LIF), a member of the family of interleukin-6-type cytokines. These cytokines activate Janus tyrosine kinases and signal transducer and activator of transcription factors (Stat) via the signalling receptor component gp130.

Induction of differentiation by IL-6-type cytokines is impaired in myeloid leukaemia cells unable to activate Stat5a.

The block of differentiation in myeloid leukaemia can be overcome by treatment with a variety of agents including cytokines. Interleukin 6 (IL-6) and leukaemia inhibitory factor (LIF) induce macrophage differentiation and growth arrest through activation of the Janus kinase (Jak)/signal transducers and activators of transcription (Stat) signal pathway in murine M1 myeloid leukaemia cells. Treatment of various other myeloid leukaemia lines with LIF or IL-6 did not lead to induction of differentiation.

Members of the family of IL-6-type cytokines activate Stat5a in various cell types.

Interleukin-6 (IL-6)-type cytokines activate transcription factors Stat1 and Stat3 (signal transducers and activators of transcription). Here we report that leukemia inhibitory factor (LIF) and IL-6 activate Stat5a in M1 myeloid leukemia cells in addition. In murine embryonal stem (ES) cells stably transfected with an expression vector for Stat5a treatment with LIF resulted in tyrosine phosphorylation and DNA-binding of this transcription factor.

Differential regulation of chemokines by leukemia inhibitory factor, interleukin-6 and oncostatin M.

M. Leukemia inhibitory factor (LIF). oncostatin M (OsM) and interleukin-6 (IL-6) are members of a cytokine family, which are produced by activated macrophages and glomerular mesangial cells.

Prolactin induction of the alpha 2-Macroglobulin gene in rat ovarian granulosa cells: stat 5 activation and binding to the interleukin-6 response element.

alpha 2-Macroglobulin (alpha 2M) is expressed at high levels in the corpus luteum of pregnant rats in response to PRL and rat placental lactogens. These studies document that PRL induction of alpha 2M mRNA occurs rapidly in granulosa cells differentiated to the preovulatory phenotype in the presence of FSH and steroid, is hormone specific [induced by PRL but not by LH or interleukin-6 (IL-6)], and involves tyrosine kinase activity. To analyze the cellular signaling events stimulated by PRL, transient transfections of granulosa cells and electrophoretic mobility shift assays were done using the IL-6 response element (IL-6RE) of the alpha 2M promoter.

Transcription factors Stat3 and Stat5b are present in rat liver nuclei late in an acute phase response and bind interleukin-6 response elements.

Proteins binding at the interleukin-6 response element of the rat alpha 2 macroglobulin gene were purified by a combination of chromatographic procedures including binding site-specific DNA-affinity chromatography as the principal step. Three polypeptides of 92, 91, and 86 kDa were enriched approximately 6,300-fold from nuclei of rat livers excised 12 h after the induction of an experimental acute phase response. Amino acid sequence analysis identified the 86- and 91-kDa species as two forms of the transcription factor Stat3 and the 92-kDa species as the factor Stat5b.

The LIF response element of the alpha 2 macroglobulin gene confers LIF-induced transcriptional activation in embryonal stem cells.

Leukaemia Inhibitory Factor (LIF), an interleukin 6 (IL-6)-type cytokine, is an essential growth factor for murine embryonal stem cells. The LIF-receptor was known in these cells, but the cell-internal part of the signal cascade and the transcription factors through which LIF controls its growth-promoting target genes in embryonal stem cells, had not been identified. This study shows that the type II IL-6-response element of the rat alpha 2 macroglobulin (alpha 2M) gene, which mediates IL-6- and LIF-responses in hepatic cells, also functioned as a LIF-response element (LIF-RE) in ES1 embryonal stem cells and P19 embryonal carcinoma cells.

Isolation of two interleukin-6 response element binding proteins from acute phase rat livers.

Proteins binding at the IL-6 response element of the rat alpha 2 macroglobulin gene were purified by a combination of conventional chromatographic procedures and binding-site specific DNA affinity chromatography. The proteins were purified from the nuclei of rat livers, excised at the peak of an experimentally induced acute phase response. By this procedure three polypeptides of 92, 91 and 86 kD were enriched more than 6,000-fold.

Cytokine-induced expression of leukemia inhibitory factor in renal mesangial cells.

Leukemia inhibitory factor (LIF) is a pleiotropic cytokine, which shares many characteristics with interleukin-6 (IL-6). Recent observations indicate a role for LIF in inflammatory processes. To examine the potential involvement of LIF in the regulation of mesangial cell behavior, we studied LIF expression in early primary cultures of rat and human mesangial cells, as well as the response of mesangial cells to exogenous LIF.

Synergistic action of interleukin-6 and glucocorticoids is mediated by the interleukin-6 response element of the rat alpha 2 macroglobulin gene.

One class of genes coding for the acute-phase proteins (acute-phase genes) is induced by interleukin 6 (IL-6) through the human transcription factor NF-IL-6 and its rat homolog IL-6-DBP/LAP. A second class, represented by the rat alpha 2 macroglobulin gene, utilizes a different IL-6 response element (IL-6-RE) and different DNA-binding proteins interacting with this element, the so-called IL-6-RE binding proteins (IL-6 RE-BPs). Human Hep3B and HepG2 hepatoma, U266 myeloma, and CESS lymphoblastoid cells contain IL-6 RE-BPs that form complexes, with the IL-6-RE, with gel mobilities indistinguishable from those of the corresponding complexes of rat liver cells.