Human myeloma cells shed the interleukin‐6 receptor: inhibition by tissue inhibitor of metalloproteinase‐3 and a hydroxamate‐based metalloproteinase inhibitor

Hargreaves, Philip G.; Wang, F.; Antcliff, J.; Murphy, Gillian; Lawry, J.; Russell, R. G. G.; Croucher, Peter I.

doi:10.1046/j.1365-2141.1998.00754.x

Cited by 83 publications

(57 citation statements)

References 46 publications

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“…TIMP-3, but neither TIMP-1 nor TIMP-2, inhibited the action of the proteinase, suggesting that the enzyme may be a membrane-associated disintegrin and metalloproteinase (ADAM), rather than a soluble MMP. Receptors for other cytokines, including IL-6 and TNF, also appear to be cleaved by ADAMs, and the shedding of those receptors is inhibited by a similar panel of inhibitors, as we have described in this study for IL-5R␣ (19,(31)(32)(33)(34)(35). Further study is required to identify the specific MMP responsible for IL-5R␣ cleavage.…”

Section: Discussionmentioning

confidence: 97%

Decreased Expression of Membrane IL-5 Receptor α on Human Eosinophils: II. IL-5 Down-Modulates Its Receptor Via a Proteinase-Mediated Process

Liu

Sedgwick

Bates

et al. 2002

The Journal of Immunology

121

106

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In the accompanying study, we demonstrated that following Ag challenge, membrane (m)IL-5Rα expression is attenuated on bronchoalveolar lavage eosinophils, soluble (s)IL-5Rα is detectable in BAL fluid in the absence of increased steady state levels of sIL-5Rα mRNA, and BAL eosinophils become refractory to IL-5 for ex vivo degranulation. We hypothesized that IL-5 regulates its receptor through proteolytic release of mIL-5Rα, which in turn contributes to the presence of sIL-5Rα. Purified human peripheral blood eosinophils were incubated with IL-5 under various conditions and in the presence of different pharmacological agents. A dose-dependent decrease in mIL-5Rα was accompanied by an increase in sIL-5Rα in the supernatant. IL-5 had no ligand-specific effect on mIL-5Rα or sIL-5Rα mRNA levels. The matrix metalloproteinase-specific inhibitors BB-94 and GM6001 and tissue inhibitor of metalloproteinase-3 partially inhibited IL-5-mediated loss of mIL-5Rα, suggesting that sIL-5Rα may be produced by proteolytic cleavage of mIL-5Rα. IL-5 transiently reduced surface expression of β-chain, but had no effect on the expression of GM-CSFRα. Pretreatment of eosinophils with a dose of IL-5 that down-modulated mIL-5Rα rendered these cells unable to degranulate in response to further IL-5 stimulation, but they were fully responsive to GM-CSF. These findings suggest that IL-5-activated eosinophils may lose mIL-5Rα and release sIL-5Rα in vivo, which may limit IL-5-dependent inflammatory events in diseases such as asthma.

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Section: Discussionmentioning

confidence: 97%

Decreased Expression of Membrane IL-5 Receptor α on Human Eosinophils: II. IL-5 Down-Modulates Its Receptor Via a Proteinase-Mediated Process

Liu

Sedgwick

Bates

et al. 2002

The Journal of Immunology

121

106

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“…This is probably because of stabilization of TNF-␣ receptors (65); TIMP-3 inhibits TNF-␣-converting enzyme (67) and IL-6 receptor shedding (68). Overexpression of TIMP-3 in rat vascular smooth muscle cells also promoted apoptosis, but this effect was independent of MMP inhibition (69).…”

Section: Timps Are Multifunctional Proteinsmentioning

confidence: 99%

Matrix Metalloproteinases

Nagase¹,

Woessner²

1999

Journal of Biological Chemistry

3,813

2,840

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The timely breakdown of extracellular matrix (ECM) 1 is essential for embryonic development, morphogenesis, reproduction, and tissue resorption and remodeling. The matrix metalloproteinases (MMPs), also called matrixins, are thought to play a central role in these processes. The expression of most matrixins is transcriptionally regulated by growth factors, hormones, cytokines, and cellular transformation (1, 2). The proteolytic activities of MMPs are precisely controlled during activation from their precursors and inhibition by endogenous inhibitors, ␣-macroglobulins, and tissue inhibitors of metalloproteinases (TIMPs). Table I lists currently known vertebrate matrixins. In addition, non-vertebrate members have been identified in sea urchins (3), Caenorhabditis elegans (4), soybean (5), and Arabidopsis thaliana (6). Most of these MMPs are the subject of individual chapters in the Handbook of Proteolytic Enzymes (7). This minireview focuses on recent progress in regulation of matrixin activities and their biological and pathological implications. Domain Structure and FunctionAll matrixins are synthesized as prepro-enzymes and secreted as inactive pro-MMPs in most cases. The primary structures of 20 vertebrate matrixins comprise several domain motifs, as illustrated in Fig. 1; the domain composition for each MMP is listed in Table I.The propeptide domain (about 80 amino acids) has a conserved unique PRCG(V/N)PD sequence. The Cys within this sequence (the "cysteine switch") ligates the catalytic zinc to maintain the latency of pro-MMPs (8, 9). This sequence is missing in MMP-23 (10). Stromelysin 3 (MMP-11), MT-MMPs, Xenopus MMP, and MMP-23 have a proprotein processing sequence RX(K/R)R at the C-terminal end of the propeptide, and MMP-11 (11) and MMP-14 (12) were shown to be activated intracellularly by furin.The catalytic domain (about 170 amino acids) contains a zinc binding motif HEXXHXXGXXH and a conserved methionine, which forms a unique "Met-turn" structure (13). This domain consists of a five-stranded ␤-sheet, three ␣-helices, and bridging loops (14). These backbone structures including the "Met-turn" are similar to those of the members from other metalloproteinase families, i.e. astacins, reprolysins (ADAMs), and serralysins; these four families constitute the "metzincins" (13). The catalytic domains of matrixins have an additional structural zinc ion and 2-3 calcium ions, which are required for the stability and the expression of enzymic activity. MMP-2 and MMP-9 have three repeats of fibronectin-type II domain inserted in the catalytic domain. These repeats interact with collagens and gelatins (15, 16).The C-terminal hemopexin-like domain (about 210 amino acids) has an ellipsoidal disk shape with a four bladed ␤-propeller structure; each blade consists of four antiparallel ␤-strands and an ␣-helix (17). The hemopexin domain is an absolute requirement for collagenases to cleave triple helical interstitial collagens (18), although the catalytic domains alone retain proteolytic activity toward other substra...

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“…Unlike TIMP-1, TIMP-2 and TIMP-3 are effective inhibitors of MT-MMPs. In contrast to the other TIMPs, TIMP-3 is capable of inhibiting the shedding of cell-membrane-anchored proteins such as tumor necrosis factor (TNF) receptor, 15 interleukin-6 receptor, 16 syndecan ectodomains, 17 and of the TNF-a-converting enzyme (TACE). 36 The presence of TIMPs has been shown in RA synovial tissue.…”

Section: Introductionmentioning

confidence: 99%

Cartilage degradation and invasion by rheumatoid synovial fibroblasts is inhibited by gene transfer of TIMP-1 and TIMP-3

Laan

Quax

Seemayer³

et al. 2003

Gene Ther

103

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Matrix metalloproteinases (MMPs) are believed to be pivotal enzymes in the invasion of articular cartilage by synovial tissue in rheumatoid arthritis (RA). Here, we investigated the effects of gene transfer of tissue inhibitors of metalloproteinases (TIMPs) on the invasiveness of RA synovial fibroblasts (RASF) in vitro and in vivo. Adenoviral vectors (Ad) were used for gene transfer. The effects of AdTIMP-1 and AdTIMP-3 gene transfer on matrix invasion were investigated in vitro in a transwell system. Cartilage invasion in vivo was studied in the SCID mouse coimplantation model for 60 days. In addition, the effects of AdTIMP-1 and AdTIMP-3 on cell proliferation were investigated. A significant reduction in invasiveness was demonstrated in vitro as well as in vivo in both the AdTIMP-1-and AdTIMP-3-transduced RASF compared with untransduced SF or SF that were transduced with control vectors. In vitro, the number of invading cells was reduced to 25% (Po0.001) in the AdTIMP-1-transduced cells and to 13% (Po0.0001) in the AdTIMP-3-transduced cells (% of untransduced cells). Cell proliferation was significantly inhibited by AdTIMP-3 and, less, by AdTIMP-1. In conclusion, overexpression of TIMP-1 and TIMP-3 by Ad gene transfer results in a marked reduction of the invasiveness of RASF in vitro and in the SCID mouse model. Apart from the inhibition of MMPs, a reduction in proliferation rate may contribute to this effect. These results suggest that overexpression of TIMPs, particularly TIMP-3 at the invasive front of pannus tissue, may provide a novel therapeutic strategy for inhibiting joint destruction in RA.

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Human myeloma cells shed the interleukin‐6 receptor: inhibition by tissue inhibitor of metalloproteinase‐3 and a hydroxamate‐based metalloproteinase inhibitor

Cited by 83 publications

References 46 publications

Decreased Expression of Membrane IL-5 Receptor α on Human Eosinophils: II. IL-5 Down-Modulates Its Receptor Via a Proteinase-Mediated Process

Decreased Expression of Membrane IL-5 Receptor α on Human Eosinophils: II. IL-5 Down-Modulates Its Receptor Via a Proteinase-Mediated Process

Matrix Metalloproteinases

Cartilage degradation and invasion by rheumatoid synovial fibroblasts is inhibited by gene transfer of TIMP-1 and TIMP-3

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