Differential shedding of the two subunits of the interleukin‐6 receptor

Mullberg, Jürgen; Dittrich, Elke; Graeve, Lutz; Gerhartz, Claudia; Yasukawa, Kiyoshi; Taga, Tetsuya; Kishimoto, Tadamitsu; Heinrich, Peter C.; Rose-John, Stefan

doi:10.1016/0014-5793(93)80507-q

Cited by 118 publications

(87 citation statements)

References 36 publications

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“…Preliminary results show an induction of sOSMR, after a phorbol ester cell contact, that is counteracted by a metalloprotease inhibitor treatment. 4 This suggests that, in addition to the exon splicing mechanism, sOSMR can also be generated by proteolytic cleavage, similarly to that previously reported for the soluble IL-6R (43)(44)(45).…”

Section: Discussionsupporting

confidence: 79%

“…Soluble IL-6 receptor is generated two different ways, shedding of the external IL-6R portion or alternative splicing, resulting in the secretion of a soluble form of receptor that lacks the transmembrane domain (43)(44)(45). Two large size signaling receptors belonging to the IL-6 family, gp130 and LIFR, have also been described as soluble products (38,46).…”

Section: Discussionmentioning

confidence: 99%

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Molecular and Functional Characterization of a Soluble Form of Oncostatin M/Interleukin-31 Shared Receptor

Diveu¹,

Véneréau

Froger

et al. 2006

Journal of Biological Chemistry

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Activation of the signaling transduction pathways mediated by oncostatin M (OSM) requires the binding of the cytokine to either type I OSM receptor (leukemia inhibitory factor receptor/ gp130) or to type II OSM receptor (OSMR/gp130). In the present work we have developed an enzyme-linked immunosorbent assay detecting a soluble form of OSMR (sOSMR) secreted by glioblastoma, hepatoma, and melanoma tumor cell lines. sOSMR was also present in sera of healthy individuals, with increased levels in multiple myeloma. Molecular cloning of a corresponding cDNA was carried out, and it encoded for a 70-kDa protein consisting of a half cytokine binding domain containing the canonical WSXWS motif, an immunoglobulinlike domain, and the first half of a second cytokine binding domain with cysteines in fixed positions. Analysis of the soluble receptor distribution revealed a preferential expression in lung, liver, pancreas, and placenta. sOSMR was able to bind OSM and interleukin-31 when associated to soluble gp130 or soluble interleukin-31R, respectively, and to neutralize both cytokine properties. We have also shown that OSM could positively regulate the synthesis of its own soluble receptor in tumor cells. Oncostatin M (OSM)3 was originally isolated from culture supernatant of U937 histiocytic leukemia cells based on its ability to inhibit the proliferation of the A375 melanoma cell line (1, 2). OSM is produced by activated monocyte, T lymphocyte, and dendritic cell types and is also described as a potent inducer of inflammation (3)(4)(5)(6)(7)(8). OSM belongs to the interleukin-6 cytokine family also encompassing IL-11, IL-27, leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), cardiotrophin-1, cardiotrophin-like cytokine, and neuropoietin (9 -12).The cytokines of the IL-6 family use two-or three-membrane subunit receptors to form high affinity receptor complexes able to mediate downstream signaling events (13-14). These receptors belong to the type I cytokine receptors, characterized by the presence of at least one cytokine binding domain (CBD) with conserved cysteine positions and a WSXWS motif (15). All the receptor complexes belonging to the IL-6 cytokine family share the common gp130 signaling receptor subunit in the formation of their multimeric receptors (16). Depending on the ligand, gp130 can either homodimerize in the presence of IL-6 or IL-11 (17, 18) or heterodimerize with related type I cytokine receptors such as LIFR, IL-27R, or OSMR when recruited by other members of the IL-6 family of cytokines (19 -21).In humans, OSM signal transduction occurs via two distinct receptor complexes. The type I OSM receptor consists of the low affinity chain, LIFR, associated to gp130 (19). This type I receptor can indifferently bind LIF or OSM. Through this mechanism, OSM elicits biological activities overlapping with those induced by LIF, such as hepatocyte activation, bone renewal, or the in vitro maintenance of embryonic stem cell phenotype (22).The type II OSM receptor, specifically recognizing OSM, associa...

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Molecular and Functional Characterization of a Soluble Form of Oncostatin M/Interleukin-31 Shared Receptor

Diveu¹,

Véneréau

Froger

et al. 2006

Journal of Biological Chemistry

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“…28 -30 Potential beneficial effects of early MMP-9 activation include removing matrix and necrotic myocytes, releasing growth factors and cell surface receptors, remodeling the extracellular matrix for scar formation, processing inflammatory mediators such as interleukin-1␤, and influencing angiogenesis. [31][32][33][34][35][36][37][38][39][40][41][42][43] An increase in MMP-9 that occurs within hours after reperfusion could serve a proactive function, with the overall result being an accelerated healing. The more focused secretion and activation of MMP-9 proposed here might obviate the danger of inappropriate proteolytic degradation.…”

Section: Functional Roles Of Mmp-9mentioning

confidence: 99%

Matrix-Dependent Mechanism of Neutrophil-Mediated Release and Activation of Matrix Metalloproteinase 9 in Myocardial Ischemia/Reperfusion

Lindsey

Wedin²,

Brown³

et al. 2001

Circulation

223

150

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Background-A key component of reperfusion of myocardial infarction is an immediate inflammatory response, which enhances tissue repair. Matrix turnover is crucial to tissue repair, and matrix metalloproteinases (MMPs) are key enzymes involved in matrix degradation. The hypothesis tested is that one inflammation-based effector of tissue repair is the secretion and activation of MMP-9 by infiltrating neutrophils. Methods and Results-Cardiac lymph and tissue were assayed for latent and active MMP-2 and MMP-9 by zymography and immunochemistry. Dual-labeling immunofluorescence determined the cellular source of MMP-9 protein. Isolated canine neutrophils were incubated with preischemic and postischemic cardiac lymph in the presence and absence of collagen-fibronectin pads, and the supernatants were assayed for latent and active MMP-9. MMP-9 increased during the first hours of reperfusion in both lymph supernatants and myocardial extracts, and this increase was of neutrophil origin. MMP-9 in the cardiac lymph remained latent but was activatable. In contrast, MMP-9 in the myocardium was in both latent and active forms. In situ zymography demonstrated that activated MMP-9 surrounded the infiltrated neutrophils. When postischemic cardiac lymph was incubated with neutrophils in vitro, MMP-9 secretion and activation occurred only in the presence of a collagen-fibronectin substrate; preischemic cardiac lymph did not induce significant secretion or activation. Conclusions-Infiltrating neutrophils are an early source of MMP-9 after reperfusion, and a portion of MMP-9 in the myocardium is active. Infiltrating neutrophils may localize MMP-9 activation by secreting MMP-9 and as a source of activating proteases.

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“…No consensus amino acid sequence has been found at the proteolytic cleavage sites of cytokine receptor and growth factor precursors identified so far [1,2]. It was demonstrated that the presence or absence of the cytoplasmic domains of the IL-6R [3] and the p60 TNFR [4] had no effect on shedding of these two proteins, whereas in the case of the p80 TNFR [5] the intracellular part of the molecule influenced the generation of the soluble receptor. Furthermore it has been found that the Cterminal valine residue of the cytoplasmic tail of TGFcc is critical for the release of this growth factor [6].…”

Section: Introductionmentioning

confidence: 96%

Further evidence for a common mechanism for shedding of cell surface proteins

et al. 1997

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Pro-TNFa, Steel factor, type IIIL-1R and IL-2Ra were expressed in COS-7 cells and the generation of their soluble forms was examined. The release of all four proteins was strongly stimulated by the phorbol ester PMA and completely blocked by a hydroxamate-based inhibitor of metalloproteases. COS-7 cell membranes were found to cleave various synthetic pro-TNFa peptides with the same specificity as a partially purified TNFot converting enzyme purified from human monocytic cells, suggesting that the same enzyme may be responsible for at least some of the COS-7 cell shedding activity.

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Differential shedding of the two subunits of the interleukin‐6 receptor

Cited by 118 publications

References 36 publications

Molecular and Functional Characterization of a Soluble Form of Oncostatin M/Interleukin-31 Shared Receptor

Molecular and Functional Characterization of a Soluble Form of Oncostatin M/Interleukin-31 Shared Receptor

Matrix-Dependent Mechanism of Neutrophil-Mediated Release and Activation of Matrix Metalloproteinase 9 in Myocardial Ischemia/Reperfusion

Further evidence for a common mechanism for shedding of cell surface proteins

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