TNF-alpha associated with fibronectin enhances phorbol myristate acetate- or antigen-mediated integrin-dependent adhesion of CD4+ T cells via protein tyrosine phosphorylation.
The effects of cytokines on immune cells may be influenced by their milieu, such as the extracellular matrix (ECM), in the vicinities of which cytokines and inflammatory cells interact and function. Previously, we demonstrated that TNF-alpha bound to fibronectin (FN) and augments the level of adhesion of activated CD4+ cells. Herein, we examined the mechanisms of this pro-adhesive activity of TNF-alpha and its putative physiologic consequences using human or rat CD4+ cells. A brief exposure of CD4+ cells to low dosages of soluble TNF-alpha or of FN- or laminin-bound TNF-alpha synergized with PMA to enhance the integrin-mediated binding of CD4+ cells to these immobilized ECM moieties. TNF-alpha-enhanced adhesion of CD4+ cells did not delay or inhibit the subsequent detachment of the cells from the substrate, and adhesion was increased provided the cells were treated with TNF-alpha immediately after their exposure to PMA. This indicates that the enhancing effect of TNF-alpha requires a previous activation of the cells. When TNF-alpha was immobilized on FN, less TNF-alpha was required to induce CD4+ cell binding to FN. Soluble, and to a greater extent FN-bound, TNF-alpha synergizes with PMA to intensify protein tyrosine phosphorylation in FN-bound CD4+ cells, and this effect of TNF-alpha was inhibited by inhibitors of tyrosine kinase. That FN-bound or soluble TNF-alpha also amplified the binding of an Ag-specific autoimmune rat T cell line to immobilized FN, emphasizes the physiologic relevance of our findings. Thus, the signal transduction and cell adhesive properties of ECM glycoproteins may be modulated upon their association with TNF-alpha, and matrix-linked TNF-alpha may recruit and direct immune cells to inflammatory sites.
Hershkoviz
R
R
Department Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Cahalon
L
L
Miron
S
S
Alon
R
R
Sapir
T
T
Akiyama
S K
SK
Yamada
K M
KM
Lider
O
O
D000818:Animals; D000941:Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D002448:Cell Adhesion; D005353:Fibronectins / Q000502:physiology*; D006801:Humans; D019012:Integrin beta1; D016023:Integrins / Q000502:physiology*; D007797:Laminin / Q000502:physiology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D051381:Rats; D011917:Rats, Inbred Lew; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000941:Antigens; D005353:Fibronectins; D019012:Integrin beta1; D016023:Integrins; D007797:Laminin; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D011505:Protein-Tyrosine Kinases; D013755:Tetradecanoylphorbol Acetate