A New Type of Cytokine Receptor Antagonist Directly Targeting gp130

Renné, Christoph; Kallen, Karl-Josef; Mullberg, Jürgen; Jostock, Thomas; Grötzinger, Joachim; Rose-John, Stefan

doi:10.1074/jbc.273.42.27213

Cited by 35 publications

(17 citation statements)

References 41 publications

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“…This is essentially the same mechanism of action that has been observed for IL-6/IL-6R signaling. Oncostatin M differs from IL-11 and IL-6 in that it directly binds to gp130 and signals through either gp130/leukemiainhibitory factor receptor ␤ or gp130/oncostatin M receptor heterodimers (51,52). Because gp130 is ubiquitously expressed, the FIGURE 10.…”

Section: Discussionmentioning

confidence: 99%

IL-11 Activates Human Endothelial Cells to Resist Immune-Mediated Injury

Mahboubi

Biedermann

Carroll³

et al. 2000

The Journal of Immunology

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IL-11, a gp130-signaling cytokine, is protective in several in vivo models of immune-mediated and inflammatory injury. HUVECs express IL-11 receptor α-chain and gp130. Human IL-11 causes rapid (2–10 min) tyrosine phosphorylation of gp130. IL-11 at 0.1 and 10 ng/ml induces tyrosine phosphorylation of STAT3 and STAT1, respectively, although maximal responses require 50 ng/ml. Phospho-STAT3 and phospho-STAT1 levels peak rapidly (2.5 min) and disappear by 60 min. The p42 and p44 mitogen-activated protein kinases (MAPKs) are phosphorylated in response to 0.3 ng/ml IL-11 with maximal activation at 30 ng/ml IL-11. Phosphorylation of p42 and p44 MAPKs, which can be prevented by a mitogen-activated protein/extracellular signal-related kinase kinase-1 inhibitor, peaks by 15–20 min and largely disappears by 40 min. IL-11 does not activate NF-κB nor does it inhibit NF-κB activation by TNF. Similarly, IL-11 neither induces E-selectin or ICAM-1 nor blocks induction by TNF. Although IL-11 does not alter class I MHC complex molecule expression, pretreatment with 0.5 ng/ml IL-11 partially protects HUVECs against lysis by allospecific class I MHC-restricted cytolytic T lymphocytes or by anti-class I MHC Ab plus heterologous C. IL-11-induced cytoprotection is protein synthesis dependent and may depend on mitogen-activated protein/extracellular signal-related kinase kinase-1. Our results indicate that low (i.e., STAT3- and MAPK-activating) concentrations of IL-11 confer resistance to immune-mediated injury in cultured HUVECs without inhibiting proinflammatory responses.

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Section: Discussionmentioning

confidence: 99%

IL-11 Activates Human Endothelial Cells to Resist Immune-Mediated Injury

Mahboubi

Biedermann

Carroll³

et al. 2000

The Journal of Immunology

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“…For example, increased levels of IL 6 (and in this case, also TNF-alpha and CRP) are associated with senile osteoporosis in both females and males (217). This may offer a possibility for pharmacological intervention by IL 6R blockade (218). Even for IL 6, however, not all investigators have found elevated serum levels in perfectly healthy elderly humans (219).…”

Section: Cytokine Production and Responsementioning

confidence: 99%

T cells and aging (update February 1999)

Pawelec

1999

Front Biosci

113

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T cell immunosenescence 218effects of dysregulated immune responses in the elderly by supplementation or other approaches may result in an enhancement of their quality of life, and significant reductions in the cost of medical care in old age. FACTORS CONTRIBUTING TO IMMUNO-SENESCENCE HematopoiesisDysregulated hematopoiesis is seen in elderly individuals, raising the possibility that this could contribute to altered immune function in the aged. Hematopoiesis in man may be compromised because of a severely reduced capacity to produce colony stimulating factors (44) and increased production of pro-inflammatory factors such as IL 6 (45), because lower numbers of progenitor cells are present in the BM (46) and because of an age-related decline in proliferative potential of putative haematopoietic stem cells (HSC) (47). In mice, the repopulating potential of murine fetal liver-derived HSC is higher than that of adult BM-derived stem cells (48), suggesting possible aging of the HSC themselves. Normal cells with shorter telomeres possess less remaining replicative capacity than those with longer telomeres (see section 5.2). Accordingly, HSC from adult BM were found to have shorter telomeres than fetal liver-derived or umbilical cord-derived stem cells, consistent with aging of HSC (49). Telomere lengths decreased on culture despite low level expression of telomerase in these cells (50,51), although the rate of basepair loss per population doubling of cells in culture was lower during the first two weeks, when telomerase was upregulated, than in the next two, when it was downregulated (52). The telomerase expressed is therefore functionally active but may not be able to completely maintain telomere length in aging HSC cells. True embryonic stem cells (ESC), on the other hand, which may really be immortal, do retain high levels of telomerase activity (53). On the other hand, ESC from telomerase-knockout mice show gradual telomere shortening over many population doublings (PD) resulting in slowing and eventual cessation of growth (54). Certain animals which do not downregulate telomerase manifest a permanent growth phase and little or no senescence (55,56).

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“…COS-7 cells were transiently transfected with p409-vIL-6 using the DEAE-dextran method (42,64). The next day, DMEM containing 10% FCS was changed to 5 ml FCS-free DMEM.…”

Section: Methodsmentioning

confidence: 99%

Abrogation of Viral Interleukin-6 (vIL-6)-Induced Signaling by Intracellular Retention and Neutralization of vIL-6 with an Anti-vIL-6 Single-Chain Antibody Selected by Phage Display

Kovaleva

Bußmeyer

Rabe

et al. 2006

J Virol

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Human herpesvirus 8 (HHV-8) encodes several putative oncogenes, which are homologues to cellular host genes known to function in cell cycle regulation, control of apoptosis, and cytokine signaling. Viral interleukin (vIL-6) is believed to play an important role in the pathogenesis of Kaposi's sarcoma as well as primary effusion lymphoma and multicentric Castleman's disease. Therefore, vIL-6 is a promising target for novel therapies directed against HHV-8-associated diseases. By phage display screening of human synthetic antibody libraries, we have selected a specific recombinant antibody, called monoclonal anti-vIL-6 (MAV), binding to vIL-6. The epitope recognized by MAV was localized on the top of the D helix of the vIL-6 protein, which is a part of receptor binding site III. Consequently, MAV specifically inhibits vIL-6-mediated growth of the primary effusion lymphoma-derived cell line BCBL-1 and blocks STAT3 phosphorylation in the human hepatoma cell line HepG2. Since it was previously found that vIL-6 can also induce signals from within the cell, presumably within the endoplasmic reticulum, we fused the recombinant antibody MAV with the endoplasmic retention sequence KDEL (MAV-KDEL). As a result, COS-7 cells expressing MAV-KDEL and synthesizing vIL-6 ceased to secrete the cytokine. Moreover, we observed that vIL-6 that was bound to MAV-KDEL and retained in the endoplasmic reticulum did not induce STAT3 phosphorylation in HepG2 cells. We conclude that the activity of the intracellularly retained vIL-6 protein is neutralized by MAV-KDEL. Our results might represent a novel therapeutic strategy to neutralize virally encoded growth factors or oncogenes.

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A New Type of Cytokine Receptor Antagonist Directly Targeting gp130

Cited by 35 publications

References 41 publications

IL-11 Activates Human Endothelial Cells to Resist Immune-Mediated Injury

IL-11 Activates Human Endothelial Cells to Resist Immune-Mediated Injury

T cells and aging (update February 1999)

Abrogation of Viral Interleukin-6 (vIL-6)-Induced Signaling by Intracellular Retention and Neutralization of vIL-6 with an Anti-vIL-6 Single-Chain Antibody Selected by Phage Display

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