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Fibronectin-bound TNF-alpha stimulates monocyte matrix metalloproteinase-9 expression and regulates chemotaxis.
J Leukoc Biol. 2000 Nov; 68(5):737-47.JL

Abstract

Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine implicated in the stimulation of matrix metalloproteinase (MMP) production by several cell types. Our previous studies demonstrated that TNF-alpha avidly binds fibronectin (FN) and laminin, major adhesive glycoproteins of extracellular matrix (ECM) and basement membranes. These findings suggested that TNF-alpha complexing to insoluble ECM components may serve to concentrate its activities to distinct inflamed sites. Herein, we explored the bioactivity and possible function of ECM-bound TNF-alpha by examining its effects on MMP-9 secretion by monocytes. Immunofluorescent staining indicated that LPS-activated monocytes deposited newly synthesized TNF-alpha into ECM-FN. FN-bound TNF-alpha (FN/TNF-alpha) significantly up-regulated MMP-9 expression and secretion by the human monocytic cell line MonoMac-6 and peripheral blood monocytes. Such secretion could be inhibited by antibodies that block TNF-alpha activity and binding to its receptors TNF RI (p55) and TNF RII (p75). Cheniotaxis through ECM gels in the presence of soluble or bound TNF-alpha was inhibited by a hydroxamic acid inhibitor of MMPs (GM6001). It is interesting that, although the adhesion of MonoMac-6 cells to FN/TNF-alpha required functional activated beta1 integrins, FN/TNF-alpha-induced MMP-9 secretion was independent of binding to beta1 integrins, since MMP-9 secretion was unaffected by: (1) neutralizing nAb to alpha4, alpha5, and beta1 subunits, which blocked cell adhesion; (2) a mAb that stimulated beta1 integrin-mediated adhesion; and (3) binding TNF-alpha to the 30-kDa amino-terminal fragment of FN, which lacks the major cell adhesive binding sites. Thus, in addition to their cell-adhesive roles, ECM glycoproteins, such as FN, may play a pivotal role in presenting proinflammatory cytokines to leukocytes within the actual inflamed tissue, thereby affecting their capacities to secrete ECM-degrading enzymes. These TNF-alpha-ECM interactions may serve to limit the cytokine's availability and bioactivity to target areas of inflammation.

Authors+Show Affiliations

Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11073115

Citation

Vaday, G G., et al. "Fibronectin-bound TNF-alpha Stimulates Monocyte Matrix Metalloproteinase-9 Expression and Regulates Chemotaxis." Journal of Leukocyte Biology, vol. 68, no. 5, 2000, pp. 737-47.
Vaday GG, Hershkoviz R, Rahat MA, et al. Fibronectin-bound TNF-alpha stimulates monocyte matrix metalloproteinase-9 expression and regulates chemotaxis. J Leukoc Biol. 2000;68(5):737-47.
Vaday, G. G., Hershkoviz, R., Rahat, M. A., Lahat, N., Cahalon, L., & Lider, O. (2000). Fibronectin-bound TNF-alpha stimulates monocyte matrix metalloproteinase-9 expression and regulates chemotaxis. Journal of Leukocyte Biology, 68(5), 737-47.
Vaday GG, et al. Fibronectin-bound TNF-alpha Stimulates Monocyte Matrix Metalloproteinase-9 Expression and Regulates Chemotaxis. J Leukoc Biol. 2000;68(5):737-47. PubMed PMID: 11073115.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fibronectin-bound TNF-alpha stimulates monocyte matrix metalloproteinase-9 expression and regulates chemotaxis. AU - Vaday,G G, AU - Hershkoviz,R, AU - Rahat,M A, AU - Lahat,N, AU - Cahalon,L, AU - Lider,O, PY - 2000/11/10/pubmed PY - 2001/2/28/medline PY - 2000/11/10/entrez SP - 737 EP - 47 JF - Journal of leukocyte biology JO - J Leukoc Biol VL - 68 IS - 5 N2 - Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine implicated in the stimulation of matrix metalloproteinase (MMP) production by several cell types. Our previous studies demonstrated that TNF-alpha avidly binds fibronectin (FN) and laminin, major adhesive glycoproteins of extracellular matrix (ECM) and basement membranes. These findings suggested that TNF-alpha complexing to insoluble ECM components may serve to concentrate its activities to distinct inflamed sites. Herein, we explored the bioactivity and possible function of ECM-bound TNF-alpha by examining its effects on MMP-9 secretion by monocytes. Immunofluorescent staining indicated that LPS-activated monocytes deposited newly synthesized TNF-alpha into ECM-FN. FN-bound TNF-alpha (FN/TNF-alpha) significantly up-regulated MMP-9 expression and secretion by the human monocytic cell line MonoMac-6 and peripheral blood monocytes. Such secretion could be inhibited by antibodies that block TNF-alpha activity and binding to its receptors TNF RI (p55) and TNF RII (p75). Cheniotaxis through ECM gels in the presence of soluble or bound TNF-alpha was inhibited by a hydroxamic acid inhibitor of MMPs (GM6001). It is interesting that, although the adhesion of MonoMac-6 cells to FN/TNF-alpha required functional activated beta1 integrins, FN/TNF-alpha-induced MMP-9 secretion was independent of binding to beta1 integrins, since MMP-9 secretion was unaffected by: (1) neutralizing nAb to alpha4, alpha5, and beta1 subunits, which blocked cell adhesion; (2) a mAb that stimulated beta1 integrin-mediated adhesion; and (3) binding TNF-alpha to the 30-kDa amino-terminal fragment of FN, which lacks the major cell adhesive binding sites. Thus, in addition to their cell-adhesive roles, ECM glycoproteins, such as FN, may play a pivotal role in presenting proinflammatory cytokines to leukocytes within the actual inflamed tissue, thereby affecting their capacities to secrete ECM-degrading enzymes. These TNF-alpha-ECM interactions may serve to limit the cytokine's availability and bioactivity to target areas of inflammation. SN - 0741-5400 UR - https://www.unboundmedicine.com/medline/citation/11073115/Fibronectin_bound_TNF_alpha_stimulates_monocyte_matrix_metalloproteinase_9_expression_and_regulates_chemotaxis_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0741-5400&date=2000&volume=68&issue=5&spage=737 DB - PRIME DP - Unbound Medicine ER -