The role of human T-lymphocyte-monocyte contact in inflammation and tissue destruction

Abstract

Contact-mediated signaling of monocytes by human stimulated T lymphocytes (TL) is a potent proinflammatory mechanism that triggers massive upregulation of the proinflammatory cytokines IL-1 and tumor necrosis factor-alpha. These two cytokines play an important part in chronic destructive diseases, including rheumatoid arthritis. To date this cell-cell contact appears to be a major endogenous mechanism to display such an activity in monocyte-macrophages. Since TL and monocyte-macrophages play a pivotal part in the pathogenesis of chronic inflammatory diseases, we investigated the possible ligands and counter-ligands involved in this cell-cell interaction. We also characterized an inhibitory molecule interfering in this process, apolipoprotein A-I. This review aims to summarize the state of the art and importance of contact-mediated monocyte activation by stimulated TL in cytokine production in rheumatoid arthritis and mechanisms that might control it.

Figure 1

Scheme of the activation cascade from T lymphocytes (T_L) to monocyte-macrophages (Mφ) and fibroblasts/synoviocytes (F/S). Activated T_L trigger Mφ to produce proinflammatory cytokines that in turn induce the production of matrix-destructive metalloproteinases (MMPs) and prostaglandin E₂ (PGE₂), the latter products being involved in cartilage destruction and bone resorption. These processes are controlled by proinflammatory factors (IL-15, IL-2, IL-18, IL-17) and anti-inflammatory factors (IL-4, IL-10, granulocyte/macrophage colony stimulating factor [GM-CSF], IFN-β). Furthermore, naturally occurring inhibitors (IL-1sRII, IL-1Ra, tumor necrosis factor [TNF]sRI, TNFsRII) inhibit the activity of IL-1 and TNF-α, the production of which is blocked by apolipoprotein (apo) A-I and decreased by exogenous antibodies to CD69 and β2-integrins (CD11b>CD11c>CD11a). APC, antigen presenting cells; DC, dendritic cells.

Figure 2

Scheme of the relationship between chronic inflammation, acute-phase proteins and homeostasis of cytokines. The liver produces both apolipoprotein (apo) A-I and serum amyloid A (SAA). IL-1β and TNF-α differentially regulate the production of acute-phase proteins by increasing the production of SAA (a proinflammatory factor) and decreasing that of apo A-I (an anti-inflammatory factor). The decreased level of apo A-I results in a better activation of monocyte-macrophages (Mφ) by direct contact with stimulated T lymphocytes (sTL), enhancing the production of IL-1 and TNF. The increased levels of SAA result in the substitution of apo A-I by SAA on high-density lipoprotein (HDL), and SAA–HDL further stimulates the production of cytokines by Mφ.

Figure 3

Apolipoprotein (apo) A-I does not significantly inhibit IL-1Ra production in peripheral blood mononuclear cells (PBMC) stimulated by either phytohemagglutinin (PHA) or tetanus toxoid (TT). Conditions: 0.4 × 10⁶ cells/well/200 μl; 5 μg/ml polymyxin; 1 μg/ml PHA; 10 μg/ml TT; 48 hour incubation for PHA, 72 hours for TT.