Suppression of IL-6 biological activities by activin A and implications for inflammatory arthropathies

Yu, Esther; Dolter, Karen E.; Shao, Li‐en; Yu, John

doi:10.1046/j.1365-2249.1998.00522.x

Cited by 92 publications

(62 citation statements)

References 28 publications

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“…It was found that the ability of the stroma to suppress the growth of plasmacytomas is due to secretion of activin A, a cytokine member of the transforming growth factor (TGF) ␤ superfamily. [20][21][22][23] This phenomenon is highly specific since other normal and tumor hemopoietic cells from different lineages were resistant to activin A. Our studies further showed that activin A kills plasmacytomas by antagonism with the survival signal of IL-6.…”

Section: Introductionsupporting

confidence: 56%

The promotion of plasmacytoma tumor growth by mesenchymal stroma is antagonized by basic fibroblast growth factor induced activin A

et al. 2001

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The mesenchymal stroma has been shown to play a crucial role in the development of multiple myeloma, partly by secretion of interleukin (IL)-6, that serves as a growth factor for myeloma cells. However, it is still unclear which other stromal molecules are involved in the pathogenesis of this disease. We chose, as a model system, a mouse plasmacytoma cell line, which does not respond to IL-6. We found that the formation of mouse plasmacytoma tumors, in an in vivo skin transplantation model, is facilitated by co-injection of these tumor cells along with a mesenchymal stromal cell. The tumor promoting effect of the stroma was reproduced in an in vitro model; stromal cells induced the proliferation of plasmacytoma cells under serumfree conditions. This growth promotion could not be mimicked by a series of cytokines including IL-6 and insulin-like growth factor (IGF)-I implying a role for yet unidentified stromal factors. The in vivo formation of plasmacytoma tumors was reduced following administration of activin A, a cytokine member of the transforming growth factor (TGF)␤ superfamily. Furthermore, the in vitro growth promoting effect of the stroma was abrogated by basic fibroblast growth factor (bFGF) which induced a higher stromal expression of activin A. Our results thus show that mesenchymal stroma expresses plasmacytoma growth stimulating activities that overcome the low constitutive level of the plasmacytoma inhibitor, activin A. The expression of activin A is upregulated by bFGF rendering the stroma suppressive for plasmacytoma growth. The balance between the expression of these regulators may contribute to mesenchymal stroma activity and influence the progression of multiple myeloma. Leukemia (2001) 15, 1102-1110.

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Section: Introductionsupporting

confidence: 56%

The promotion of plasmacytoma tumor growth by mesenchymal stroma is antagonized by basic fibroblast growth factor induced activin A

et al. 2001

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“…Activin is produced at sites of inflammation (31)(32)(33) and has been shown to play a role in wound healing in mice (34). It may also be involved in bone formation since inhibin ␤A-chain knockout mice have craniofacial abnormalities (35).…”

Section: Discussionmentioning

confidence: 99%

Proteomic Analysis of Articular Cartilage Shows Increased Type II Collagen Synthesis in Osteoarthritis and Expression of Inhibin βA (Activin A), a Regulatory Molecule for Chondrocytes

Hermansson

Sawaji

Bolton

et al. 2004

Journal of Biological Chemistry

156

141

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We show that proteomic analysis can be applied to study cartilage pathophysiology. Proteins secreted by articular cartilage were analyzed by two-dimensional SDS-PAGE and mass spectrometry. Cartilage explants were cultured in medium containing [ 35 S]methionine/cysteine to radiolabel newly synthesized proteins. To resolve the cartilage proteins by two-dimensional electrophoresis, it was necessary to remove the proteoglycan aggrecan by precipitation with cetylpyridinium chloride. 50 -100 radiolabeled protein spots were detected on two-dimensional gels of human cartilage cultures. Of 170 silverstained proteins identified, 19 were radiolabeled, representing newly synthesized gene products. Most of these were known cartilage constituents. Several nonradiolabeled cartilage proteins were also detected. The secreted protein pattern of explants from 12 osteoarthritic joints (knee, hip, and shoulder) and 14 nonosteoarthritic adult joints were compared. The synthesis of type II collagen was strongly up-regulated in osteoarthritic cartilage. Normal adult cartilage synthesized little or no type II collagen in contrast to infant and juvenile cartilage. Potential regulatory molecules novel to cartilage were identified; pro-inhibin ␤A and processed inhibin ␤A (which dimerizes to activin A) were produced by all the osteoarthritic samples and half of the normals. Connective tissue growth factor and cytokine-like protein C17 (previously only identified as an mRNA) were also found. Activin induced the tissue inhibitor for metalloproteinases-1 in human chondrocytes. Its expression was induced in isolated chondrocytes by growth factors or interleukin-1. We conclude that type II collagen synthesis in articular cartilage is down-regulated at skeletal maturity and reactivated in osteoarthritis in attempted repair and that activin A may be an anabolic factor in cartilage. Osteoarthritis (OA)1 is a common joint disease characterized by degeneration of articular cartilage. Since cartilage has very limited capacity for repair, the loss is effectively irreversible. Prevalence studies show that most people over the age of 65 have some evidence of the disease (1, 2). Little is known about the molecular mechanism of cartilage destruction in OA, particularly the early events. It is thought that there is an imbalance between anabolism and catabolism of the extracellular matrix, there being an increase in catabolism. It has been suggested that this increased breakdown of matrix is due to the production of degradative enzymes such as the matrix metalloproteinases (MMPs) and members of the disintegrin and metalloproteinase (ADAM) family (3, 4). The increase in proteinase expression may be due to inflammatory cytokines such as interleukin-1 (Il-1) and tumor necrosis factor (4, 5). However, it is unclear whether these degradative processes are a primary event or a secondary reaction.Articular cartilage consists mainly of extracellular matrix, the principal organic components of which are type II collagen fibers and aggregates of the large proteoglycan...

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“…Activins/inhibins are evolutionarily conserved, broadly distributed, 48 and influence many other processes, including inflammation, acute phase reaction, 49 proliferation and cell growth, 50 nerve cell survival and differentiation, 51,52 tissue repair and wound healing, 53,54 angiogenesis 55 and matrix and bone remodeling via BMPs (eg inhibition of osteoclastic cathepsin K-mediated bone reabsorption). [56][57][58][59][60][61] A role of activin in the pathogenesis of inflammatory arthropathies has been suggested by Yu et al 62 The latter demonstrated significantly elevated levels of activin A in the synovial fluid of patients with rheumatoid arthritis and gout, relative to those with osteoarthritis. The production of activin A by synoviocytes and chondrocytes in culture is up-regulated by cytokines such as IL-1, TGF-␤, interferon-␥, and IL-8.…”

Section: Figure 5 Real-time Pcr For Activin and Follistatin Real-timmentioning

confidence: 99%

Inhibition of cartilage destruction by double gene transfer of IL-1Ra and IL-10 involves the activin pathway

et al. 2002

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Suppression of IL-6 biological activities by activin A and implications for inflammatory arthropathies

Cited by 92 publications

References 28 publications

The promotion of plasmacytoma tumor growth by mesenchymal stroma is antagonized by basic fibroblast growth factor induced activin A

The promotion of plasmacytoma tumor growth by mesenchymal stroma is antagonized by basic fibroblast growth factor induced activin A

Proteomic Analysis of Articular Cartilage Shows Increased Type II Collagen Synthesis in Osteoarthritis and Expression of Inhibin βA (Activin A), a Regulatory Molecule for Chondrocytes

Inhibition of cartilage destruction by double gene transfer of IL-1Ra and IL-10 involves the activin pathway

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