Tumour necrosis factor-alpha interacts with laminin and functions as a pro-adhesive cytokine.

Abstract

Certain cytokines, chemokines and growth factors interact with components of the extracellular matrix (ECM) and, in particular, sulphated polysaccharides and proteoglycans. Recently, we demonstrated that tumour necrosis factor-alpha (TNF-alpha), an inflammatory cytokine, can bind fibronectin (FN), a cell-adhesive glycoprotein of the ECM, and that TNF-alpha bound to FN enhances the binding of T cells to the glycoprotein. In the present study, we studied the interactions of TNF-alpha and laminin (LN), another glycoprotein present in basement membranes and extracellular matrices. 125I-labelled TNF-alpha was found to bind to immobilized LN, and more avidly to the E1 and P1 fragments of LN, which contain its integrin- and non-integrin-dependent cell-adhesive sites, suggesting that cryptic TNF-alpha-binding sites are exposed upon proteolytic fragmentation of LN by enzymes such as elastase or pepsin. The bound cytokine did not dissociate from the LN and its fragments during a 24-hr period, indicating that in vivo LN can serve to restrict TNF-alpha adjacent to inflammatory sites. The LN-associated TNF-alpha retained at least some of its biological activities, since both diffusible and, to a greater extent, LN-bound TNF-alpha elevated the beta 1-integrin-dependent adhesion to LN of phorbol ester-activated human CD4+ T cells. Thus, LN and TNF-alpha may act in concert to transmit synergistic activating signals to infiltrating leucocytes, and thereby regulate immune cell reactions in extravascular inflammatory tissue.