Analysis of IL-6-mediated growth control of myeloma cells using a gp130 chimeric receptor approach

French, Jena D.; Tschumper, Renee C.; Jelinek, Diane F.

doi:10.1038/sj.leu.2402516

Cited by 15 publications

(21 citation statements)

References 32 publications

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“…Stat3 protein plays a central role in transmitting a multitude of different processes initiated by the IL-6 cytokine family (French et al, 2002). Moreover, IL-6 has been shown to mediate expression of C5aR in several cell types (Riedemann et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Urokinase-induced activation of the gp130/Tyk2/Stat3 pathway mediates a pro-inflammatory effect in human mesangial cells via expression of the anaphylatoxin C5a receptor

Shushakova

Tkachuk

Dangers

et al. 2005

Journal of Cell Science

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Glomerular mesangial cells (MCs) are central to the pathogenesis of progressive glomeruli-associated renal diseases. However, molecular mechanisms underlying changes in MC functions still remain poorly understood. Here, we show that in MCs, the urokinase-type plasminogen activator (uPA) induces, via its specific receptor (uPAR, CD87), upregulated expression of the complement anaphylatoxin C5a receptor (C5aR, CD88), and modulates C5a-dependent functional responses. This effect is mediated via the interaction of the uPA-specific receptor (uPAR, CD87) and gp130, a signal transducing subunit of the receptor complexes for the IL-6 cytokine family. The Janus kinase Tyk2 and the transcription factor Stat3 serve as downstream components in the signaling cascade resulting in upregulation of C5aR expression. In vivo, expression of C5aR and uPAR was increased in the mesangium of wild-type mice in a lipopolysaccharide (LPS)-induced model of inflammation, whereas in uPAR–/– animals C5aR expression remained unchanged. This is the first demonstration in vitro and in vivo that uPA acts in MCs as a modulator of immune responses via control of immune-competent receptors. The data suggest a novel role for uPA/uPAR in glomeruli-associated renal failure via a signaling cross-talk between the fibrinolytic and immune systems.

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Section: Discussionmentioning

confidence: 99%

Urokinase-induced activation of the gp130/Tyk2/Stat3 pathway mediates a pro-inflammatory effect in human mesangial cells via expression of the anaphylatoxin C5a receptor

Shushakova

Tkachuk

Dangers

et al. 2005

Journal of Cell Science

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“…1A). IL-6 is a proinflammatory cytokine shown to be important for the biology of normal and malignant B cells (10,(31)(32)(33)(34)(35)(36)(37)(38)(39). Characterization of this phenomenon revealed that CCL5-induced IL-6 secretion was accompanied by an increase in IL-6 mRNA levels and promoter activity (Fig.…”

Section: Ccl5 Modulates Il-6 Expression and Secretion In Wm Stromal Cmentioning

confidence: 99%

“…IL-6 is a known modulator of the biology of normal and malignant B cells, including immunoglobulin secretion (36,38,45). We initially examined the ability of IL-6 to modulate IgM secretion in WM.…”

Section: Cells and Cd19ϩmentioning

confidence: 99%

GLI2 Transcription Factor Mediates Cytokine Cross-talk in the Tumor Microenvironment

Elsawa

Almada

Ziesmer

et al. 2011

Journal of Biological Chemistry

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Tumor cells interact with their surrounding microenvironment to survive and persist within the host. Cytokines play a key role in regulating this crosstalk between malignant cells and surrounding cells in the microenvironment. Although this phenomenon is clearly established, the molecular mechanisms mediating this cellular event remain elusive. Here, using as a model bone marrow stromal cells, we describe a novel signaling mechanism initiated by CCL5 in these cells leading to up-regulation of immunoglobulin secretion by malignant B cells. CCL5 increases IL-6 expression and secretion in bone marrow stromal cells. IL-6 in turn induces Ig secretion by malignant B cells. Analysis of the mechanism reveals that CCL5 signaling induces GLI2 through a PI3K-AKT-IB␣-p65 pathway and requires GLI2 transcriptional activity to modulate IL-6 expression and Ig secretion in vitro and in vivo. Together, these results identify a novel signaling pathway mediating the stromal-cancer cell interactions, leading to increased Ig production by malignant cells.

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“…During the course of our studies on myeloma cell growth control (French et al, 2002), we serendipitously discovered that the KAS-6/1 cell line expressed mRNA for ErbB3. ErbB3, as well as the other three members of the ErbB receptor family have molecular weights in the range of 170-190 kDa.…”

Section: Myeloma Cell Expression Of Erbb Family Membersmentioning

confidence: 99%

Atypical expression of ErbB3 in myeloma cells: cross-talk between ErbB3 and the interferon-α signaling complex

et al. 2003

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We have previously demonstrated that the responsiveness of multiple myeloma (MM) cells to interferon-alpha (IFN-a) stimulation is variable, with an atypical growth response displayed by some cells. Here we report the ability of IFN-a to induce tyrosine phosphorylation of a 180 kDa band in the KAS-6/1 MM cell line, which is growth responsive to IFN-a. Further characterization demonstrated that this band corresponds to ErbB3. To our knowledge, this is the first report of ErbB3 expression in a cell type of the hematopoietic lineage. Although ErbB receptors have been shown to crosscommunicate with various other receptors, our results show for the first time that the IFN-a receptor can crosscommunicate with ErbB3. To address the significance of these observations, we transfected ErbB3-negative DP-6 MM cells with ErbB3 and used siRNA to silence ErbB3 in the KAS-6/1 cell line. Although IFN-a transactivated ErbB3 in the DP-6 transfectants, it did not confer growth responsiveness to IFN-a. Interestingly, silencing ErbB3 expression in the KAS-6/1 cells decreased the overall growth response to IFN-a and to interleukin-6. These results suggest that ErbB3 expression alone does not uniquely confer IFN-a growth responsiveness, but instead may amplify proliferation rates in MM cells that have acquired atypical expression of this receptor.

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Analysis of IL-6-mediated growth control of myeloma cells using a gp130 chimeric receptor approach

Cited by 15 publications

References 32 publications

Urokinase-induced activation of the gp130/Tyk2/Stat3 pathway mediates a pro-inflammatory effect in human mesangial cells via expression of the anaphylatoxin C5a receptor

Urokinase-induced activation of the gp130/Tyk2/Stat3 pathway mediates a pro-inflammatory effect in human mesangial cells via expression of the anaphylatoxin C5a receptor

GLI2 Transcription Factor Mediates Cytokine Cross-talk in the Tumor Microenvironment

Atypical expression of ErbB3 in myeloma cells: cross-talk between ErbB3 and the interferon-α signaling complex

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