Activated gp130 signaling selectively targets B cell differentiation to induce mature lymphoma and plasmacytoma

Scherger, Anna Katharina; Al-Maarri, Mona; Maurer, H. Carlo; Schick, Markus; Maurer, Sabine; Öllinger, Rupert; González-Menéndez, Irene; Martella, Manuela; Thaler, Markus; Pechloff, Konstanze; Steiger, Katja; Sander, Sandrine; Ruland, Jürgen; Rad, Roland; Quintanilla-Martı́nez, Leticia; Wunderlich, Frank; Rose–John, Stefan; Keller, Ulrich

doi:10.1172/jci.insight.128435

Cited by 22 publications

(22 citation statements)

References 51 publications

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“…In these mice, by breeding to an appropriate cre transgenic mouse, the L-gp130 molecule can be switched on constitutively in a cell autonomous manner. Activating gp130 in B-cells or in the entire hematopoietic system resulted in B-cell lymphomas and plasma cell disorders with full penetrance [39]. These mice will be useful in the future to study many more cell-specific activities of IL-6 without confounding activities of other cells or tissues.…”

Section: Introductionmentioning

confidence: 99%

ADAM17 Activity and IL-6 Trans-Signaling in Inflammation and Cancer

Schumacher

Rose–John

2019

Cancers

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All ligands of the epidermal growth factor receptor (EGF-R) are transmembrane proteins, which need to be proteolytically cleaved in order to be systemically active. The major protease responsible for this cleavage is the membrane metalloprotease ADAM17, which also has been implicated in cleavage of TNFα and interleukin-6 (IL-6) receptor. It has been recently shown that in the absence of ADAM17, the main protease for EGF-R ligand processing, colon cancer formation is largely abrogated. Intriguingly, colon cancer formation depends on EGF-R activity on myeloid cells rather than on intestinal epithelial cells. A major activity of EGF-R on myeloid cells is the stimulation of IL-6 synthesis. Subsequently, IL-6 together with the ADAM17 shed soluble IL-6 receptor acts on intestinal epithelial cells via IL-6 trans-signaling to induce colon cancer formation, which can be blocked by the inhibitor of IL-6 trans-signaling, sgp130Fc. Blockade of IL-6 trans-signaling therefore offers a new therapeutic window downstream of the EGF-R for the treatment of colon cancer and possibly of other EGF-R related neoplastic diseases.

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Section: Introductionmentioning

confidence: 99%

ADAM17 Activity and IL-6 Trans-Signaling in Inflammation and Cancer

Schumacher

Rose–John

2019

Cancers

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“…We generated mice with a Creinducible expression cassette in the ROSA26 locus. When Lgp130 was expressed in B-cells, it was sufficient to drive B-cell malignancies [100]. However, when Lgp130 was expressed in hepatocytes, we did not observe tumour formation in aged mice, despite persistent gp130/STAT3 activation [28].…”

Section: Effect Of Il-6 On (Pre-)malignant Hepatic Cellsmentioning

confidence: 57%

The two facets of gp130 signalling in liver tumorigenesis

2021

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The liver is a vital organ with multiple functions and a large regenerative capacity. Tumours of the liver are the second most frequently cause of cancer-related death and develop in chronically inflamed livers. IL-6-type cytokines are mediators of inflammation and almost all members signal via the receptor subunit gp130 and the downstream signalling molecule STAT3. We here summarize current knowledge on how gp130 signalling and STAT3 in tumour cells and cells of the tumour micro-environment drives hepatic tumorigenesis. We furthermore discuss very recent findings describing also anti-tumorigenic roles of gp130/STAT3 and important considerations for therapeutic interventions.

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“…During inflammatory states, IL-6 is secreted by many cell types including myeloid cells, fibroblasts, endothelial cells and T-cells ( Kang et al, 2020 ) and the response to IL-6 stimulation differs between cell types ( Jones and Jenkins, 2018 ). In order to define the cell specific response to IL-6 we have generated a constitutively activated GP130 molecule, which was dimerized by a leucine zipper ( Stuhlmann-Laeisz et al, 2006 ) and inserted this construct, which we termed LGP130, into the ROSA26 locus of mice ( Scherger et al, 2019 ). This mouse model allows to activate GP130 signaling in a cell-autonomous manner in every selected cell type by breeding these mice to appropriate Cre-expressing transgenic mice ( Haldar et al, 2007 ; Scherger et al, 2019 ).…”

Section: The Interleukin-6 Family Of Cytokinesmentioning

confidence: 99%

“…In order to define the cell specific response to IL-6 we have generated a constitutively activated GP130 molecule, which was dimerized by a leucine zipper ( Stuhlmann-Laeisz et al, 2006 ) and inserted this construct, which we termed LGP130, into the ROSA26 locus of mice ( Scherger et al, 2019 ). This mouse model allows to activate GP130 signaling in a cell-autonomous manner in every selected cell type by breeding these mice to appropriate Cre-expressing transgenic mice ( Haldar et al, 2007 ; Scherger et al, 2019 ). This mouse model allowed us recently to define the interplay of cell-autonomous, activated GP130 in hepatocytes and a systemic innate immune response, which was likely triggered by the hepatic GP130-induced expression of acute phase proteins such as serum amyloid A ( Schumacher et al, 2021 ).…”

Section: The Interleukin-6 Family Of Cytokinesmentioning

confidence: 99%

Endosomes as Signaling Platforms for IL-6 Family Cytokine Receptors

Schmidt-Arras

Rose–John

2021

Front. Cell Dev. Biol.

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Interleukin-6 (IL-6) is the name-giving cytokine of a family of eleven members, including IL-6, CNTF, LIF, and IL-27. IL-6 was first recognized as a B-cell stimulating factor but we now know that the cytokine plays a pivotal role in the orchestration of inflammatory processes as well as in inflammation associated cancer. Moreover, IL-6 is involved in metabolic regulation and it has been shown to be involved in major neural activities such as neuroprotection, which can help to repair and to reduce brain damage. Receptor complexes of all members formed at the plasma membrane contain one or two molecules of the signaling receptor subunit GP130 and the mechanisms of signal transduction are well understood. IL-6 type cytokines can also signal from endomembranes, in particular the endosome, and situations have been reported in which endocytosis of receptor complexes are a prerequisite of intracellular signaling. Moreover, pathogenic GP130 variants were shown to interfere with spatial activation of downstream signals. We here summarize the molecular mechanisms underlying spatial regulation of IL-6 family cytokine signaling and discuss its relevance for pathogenic processes.

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Activated gp130 signaling selectively targets B cell differentiation to induce mature lymphoma and plasmacytoma

Cited by 22 publications

References 51 publications

ADAM17 Activity and IL-6 Trans-Signaling in Inflammation and Cancer

ADAM17 Activity and IL-6 Trans-Signaling in Inflammation and Cancer

The two facets of gp130 signalling in liver tumorigenesis

Endosomes as Signaling Platforms for IL-6 Family Cytokine Receptors

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