Expression and cleavage of tumor necrosis factor‐α and tumor necrosis factor receptors by human monocytic cell lines upon direct contact with stimulated T cells

Abstract

Tumor necrosis factor-alpha (TNF-alpha) is a potent cytokine in inflammatory processes. A variety of mechanisms that modulate its activity have been described, one being its binding to soluble receptors (sTNFR). In this study, we demonstrate that human monocytic cells such as THP-1 respond to direct contact with a membrane preparation of stimulated HUT-78 cells by producing TNF-alpha and by releasing sTNFR-p75, but not sTNFR-p55, with different kinetics. TNF-alpha concentration peaked after 12 h of contact and then decreased, whereas sTNFR-p75 production increased progressively upon cell/cell contact. The decrease in TNF-alpha concentration is not due to trapping of TNF-alpha by its soluble receptors or other soluble or cell-associated molecules, but rather to a proteolytic activity associated to THP-1 cells. On the other hand, the increase in sTNFR-p75 release does not result from an increase in the cleavage of pre-existing cell-associated sTNFR-p75 but from an increase in TNFR-p75 expression, immediately followed by the cleavage of its extracellular domain. Phenylmethylsulfonylfluoride, a serine protease inhibitor, has a negative effect on both TNF-alpha degradation and sTNFR-p75 release by THP-1 cells. Thus, there may be an enzymatic activity associated to THP-1 cells that plays an important role in the neutralization of TNF-alpha activity both by degrading the molecule and by cleaving its receptors at the cell surface.

Different Modes of IL-10 and TGF-β to Inhibit Cytokine-Dependent IFN-γ Production: Consequences for Reversal of Lipopolysaccharide Desensitization

“…We noticed that TNF-␣ and IL-1␤ are produced at significant levels in our IL-12/IL-18 stimulation model, which could be caused by cell-cell contact between activated T cells and monocytes (40,41). The production of both cytokines was inhibited by IL-10 but not by TGF-␤ (data not shown).…”

A Novel Therapeutic Approach Targeting Articular Inflammation Using the Filarial Nematode-Derived Phosphorylcholine-Containing Glycoprotein ES-62

“…Synovial T cell populations contain oligoclonal subsets and several autoantigens have been identified to which synovial T cells exhibit enhanced responses (15,16). T cell effector function may be via cytokine secretion, e.g., IFN-␥ or IL-17, or through cell contactdependent cognate interactions with macrophages via ligand pairs such as LFA-1/ICAM-1 and CD40/CD154 (17)(18)(19)(20)(21)(22). Most data therefore suggest that RA is mediated via a type 1 T cell (Th1) response associated with excess monokine production (23)(24)(25)(26)(27).…”

Enhancement ofMycobacterium tuberculosis-Induced Tumor Necrosis Factor Alpha Production from Primary Human Monocytes by an Activated T-Cell Membrane-Mediated Mechanism

“…Direct contact with T cells in vitro, even in the presence of anticytokine antibodies or emetine, stimulates macrophage antimycobacterial functions, while supernatants of these cells have little effect (36,39). Other monocyte functions, including TNF-␣ secretion, can be stimulated, in the absence of cofactors, by activated T cells which have been washed and then fixed in paraformaldehyde (fixed activated T cells [FAT]) (47,48). Direct cell-cell contact is required for such stimulation, and in sites of inflammation, especially in the granuloma, such intercellular contact is common.…”