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Fibronectin‐bound TNF‐α stimulates monocyte matrix metalloproteinase‐9 expression and regulates chemotaxis

G. G. Vaday,R. Hershkoviz,M. Rahat,N. Lahat,L. Cahalon,O. Lider

Published 2000 in Journal of Leukocyte Biology

ABSTRACT

Tumor necrosis factor α (TNF‐α) is a proinflammatory cytokine implicated in the stimulation of matrix metalloproteinase (MMP) production by several cell types. Our previous studies demonstrated that TNF‐α avidly binds fibronectin (FN) and laminin, major adhesive glycoproteins of extracellular matrix (ECM) and basement membranes. These findings suggested that TNF‐α 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‐α by examining its effects on MMP‐9 secretion by monocytes. Immunofluorescent staining indicated that LPS‐activated monocytes deposited newly synthesized TNF‐α into ECM‐FN. FN‐bound TNF‐α (FN/TNF‐α) 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‐α activity and binding to its receptors TNF RI (p55) and TNF RII (p75). Chemotaxis through ECM gels in the presence of soluble or bound TNF‐α was inhibited by a hydroxamic acid inhibitor of MMPs (GM6001). It is interesting that, although the adhesion of MonoMac‐6 cells to FN/TNF‐α required functional activated β1 integrins, FN/TNF‐α‐induced MMP‐9 secretion was independent of binding to β1 integrins, since MMP‐9 secretion was unaffected by: (1) neutralizing mAb to α4, α5, and β1 subunits, which blocked cell adhesion; (2) a mAb that stimulated β1 integrin‐mediated adhesion; and (3) binding TNF‐α 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‐α‐ECM interactions may serve to limit the cytokine’s availability and bioactivity to target areas of inflammation.

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