Interleukin‐6: Structure‐function relationships

Simpson, Richard J.; Hammacher, Annet; Smith, David K.; Matthews, J.M.; Ward, Larry D.

doi:10.1002/pro.5560060501

Cited by 336 publications

(271 citation statements)

References 335 publications

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“…A role for IL-6 in haemostasis and angiogenesis in cancer R Salgado et al regulation and is produced by epithelial, bone marrow and blood borne cells (Borden and Chin, 1994;Simpson et al, 1997;Hirano, 1999). Several studies have elaborated on the prognostic impact of circulating IL-6.…”

Section: Molecular and Cellular Pathologymentioning

confidence: 99%

Arterio-venous gradients of IL-6, plasma and serum VEGF and D-dimers in human cancer

et al. 2002

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The circulating angiogenic factors vascular endothelial growth factor-A, interleukin-6 and the fibrin D-dimer fragment were measured in the mesenteric vein, the uterine vein, as well as in peripheral venous and arterial samples in 21 randomly selected patients with operable colorectal, ovarian and cervical carcinoma. In addition, immunohistochemistry for vascular endothelial growth factor-A and interleukin-6 was performed on colorectal tumours of such patients. Serum and plasma vascular endothelial growth factor-A were not significantly elevated in the vein draining the tumours, despite tumour cell expression of vascular endothelial growth factor-A. Serum vascular endothelial growth factor-A is therefore not all tumour-derived. In contrast, serum interleukin-6 was highly elevated in the draining veins in agreement with expression of interleukin-6 in the cytoplasm of tumour cells. In the megakaryoblastic cell line MEG-01, the expression of vascular endothelial growth factor-A was found to be regulated by interleukin-6. Thus, the higher platelet vascular endothelial growth factor-A load resulting in higher serum vascular endothelial growth factor levels in cancer patients may partly result from an interleukin-6 mediated upregulation of the expression of vascular endothelial growth factor-A in the precursor of the platelet, i.e. the megakaryocyte. We also confirmed by immunohistochemistry that platelets adhere and aggregate on tumour endothelium. We propose that interleukin-6 indirectly promotes tumour angiogenesis through its up-regulation of the vascular endothelial growth factor-A load in platelets. In addition, the correlations found between peripheral venous interleukin-6 and peripheral venous fibrinogen and D-dimers levels, and the high D-dimer levels found in the draining vein of the tumour, in agreement with fibrin deposits found in the tumour stroma, suggest an important role for interleukin-6 in extra-vascular fibrinogen metabolism. Our results suggest a pivotal role for interleukin-6 in the intrinsic link between haemostasis and angiogenesis. This might be of importance in the development of anti-angiogenic agents based on interference with haemostasis.

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Section: Molecular and Cellular Pathologymentioning

confidence: 99%

Arterio-venous gradients of IL-6, plasma and serum VEGF and D-dimers in human cancer

et al. 2002

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“…[9][10][11] The interaction of IL-6 with its receptor complex can trigger the activation of the mitogen-activated protein kinase (MAPK) pathways involved in the regulation of cell proliferation. 12 We have recently shown the constitutive presence of both p38 MAPK and p44/p42 MAPK activity in nonmalignant human cholangiocytes.…”

mentioning

confidence: 99%

Inhibition of interleukin 6-mediated mitogen-activated protein kinase activation attenuates growth of a cholangiocarcinoma cell line

et al. 1999

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Biliary tract malignancies represent challenges because of the lack of effective therapy and poor prognosis, in part because of the paucity of information regarding the mechanisms regulating their growth. We have recently identified a critical role for the p44/p42 mitogen-activated protein kinase (MAPK) pathway in interleukin 6 (IL-6)-stimulated growth of human cholangiocytes. Although IL-6 is a potential mitogen for cholangiocarcinoma, the role of this cytokine and its intracellular signaling pathways in cholangiocarcinoma growth is unknown. Thus, our aims were to determine the role of IL-6-mediated signaling mechanisms, and in particular the MAPK pathways, in the growth regulation of human cholangiocarcinoma.

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“…Site-directed mutagenesis of IL-6 led to the identification of three distinct epitopes (sites) responsible for the interaction with IL-6R (site I) and the two gp130 molecules (sites II and III) (30). Similarly positioned receptor-engaging epitopes have been described for the closely related cytokines IL-11 (31,32) and CNTF (33), which signal via gp130/gp130 homodimers and gp130/LIFR heterodimers, respectively.…”

Section: Discussionmentioning

confidence: 93%

“…By using soluble receptor proteins, two groups have provided experimental evidence for a hexameric complex consisting of two molecules of each IL-6, sIL-6R, and sgp130 (14,15). The data led to the proposal of two models for the architecture of the (IL-6/sIL-6R/ sgp130) 2 ternary complex (14,30). Apart from differences in minor details, both models postulate contacts between IL-6 site I to the respective sIL-6R and, more importantly, demand two topologically separated contact epitopes on each sgp130: one engaging site II of one IL-6; and a second providing contacts to site III of the other IL-6.…”

Section: Discussionmentioning

confidence: 99%

Two Different Epitopes of the Signal Transducer gp130 Sequentially Cooperate on IL-6-Induced Receptor Activation

Pflanz

Kurth

Grötzinger

et al. 2000

The Journal of Immunology

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Cytokines are key mediators for the regulation of hemopoiesis and the coordination of immune responses. They exert their various functions through activation of specific cell surface receptors, thereby initiating intracellular signal transduction cascades which lead to defined cellular responses. As the common signal-transducing receptor subunit of at least seven different cytokines, gp130 is an important member of the family of hemopoietic cytokine receptors which are characterized by the presence of at least one cytokine-binding module. Mutants of gp130 that either lack the Ig-like domain D1 (ΔD1) or contain a distinct mutation (F191E) within the cytokine-binding module have been shown to be severely impaired with respect to IL-6 induced signal transduction. After cotransfection of COS-7 cells with a combination of both inactive gp130 mutants, signal transduction in response to IL-6 is restored. Whereas cells transfected with ΔD1 do not bind IL-6/sIL-6R complexes, cells transfected with the F191E mutant bind IL-6/sIL-6R with low affinity. Combination of ΔD1 and F191E, however, leads to high-affinity ligand binding. These data suggest that two different gp130 epitopes, one on each receptor chain, sequentially cooperate in asymmetrical binding of IL-6/IL-6R in a tetrameric signaling complex. On the basis of our data, a model for the mechanism of IL-6-induced gp130 activation is proposed.

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Interleukin‐6: Structure‐function relationships

Cited by 336 publications

References 335 publications

Arterio-venous gradients of IL-6, plasma and serum VEGF and D-dimers in human cancer

Arterio-venous gradients of IL-6, plasma and serum VEGF and D-dimers in human cancer

Inhibition of interleukin 6-mediated mitogen-activated protein kinase activation attenuates growth of a cholangiocarcinoma cell line

Two Different Epitopes of the Signal Transducer gp130 Sequentially Cooperate on IL-6-Induced Receptor Activation

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