Cytokine stimulation of T lymphocytes regulates their capacity to induce monocyte production of tumor necrosis factor-alpha, but not interleukin-10: possible relevance to pathophysiology of rheumatoid arthritis

Eur J Immunol. 1997 Mar;27(3):624-32. doi: 10.1002/eji.1830270308.


Previous studies in the laboratory have shown that the pro-inflammatory cytokine tumor necrosis factor (TNF)-alpha plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA). The mechanisms involved in regulating monocyte/macrophage cytokine production are not yet fully understood, but are thought to involve both soluble factors and cell/cell contact with other cell types. We and others have previously demonstrated that T cells activated through the T cell receptor/CD3 complex induce monocyte TNF-alpha production by contact-mediated signals. In this report, we investigated further whether T cells activated by cytokines in the absence of T cell receptor stimulation also regulate monocyte cytokine production. T cells were activated in an antigen-independent manner using the cytokines interleukin (IL)-15 or IL-2 alone, or in combination with IL-6 and TNF-alpha. Subsequently, T cells were fixed and incubated with monocytes. Fixed, cytokine-stimulated T cells induced monocytes to secrete TNF-alpha in a dose-dependent manner, but did not induce secretion of IL-10, a potent endogenous down-regulator of TNF-alpha and other pro-inflammatory cytokines. Stimulation of monocyte TNF-alpha was markedly inhibited when T cells were physically separated from monocytes within the tissue culture well, confirming that T cell contact is necessary. T cell acquisition of monocyte-activating capacity was shown to be dependent on the period of cytokine stimulation, with T cells activated for 8 days more effective than T cells activated for shorter periods. Addition of interferon-gamma or granulocyte/macrophage colony-stimulating factor to the T cell/monocyte cultures enhanced T cell induction of monocyte TNF-alpha by threefold and ninefold, respectively. The results from this model of cognate interaction suggest that cytokine-stimulated T cells, interacting with macrophages in the rheumatoid synovial membrane, may contribute to the continuous excessive production of TNF-alpha observed in the RA joint, and to the imbalance of pro-inflammatory cytokines over anti-inflammatory cytokines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Surface / analysis
  • Arthritis, Rheumatoid / immunology*
  • Cell Communication
  • Cells, Cultured
  • Cytokines / physiology*
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • Humans
  • Immunophenotyping
  • Interferon-gamma / pharmacology
  • Interleukin-10 / immunology*
  • Interleukin-15 / pharmacology
  • Interleukin-2 / pharmacology
  • Interleukin-6 / pharmacology
  • Monocytes / immunology*
  • Monocytes / metabolism
  • T-Lymphocytes / immunology*
  • Tumor Necrosis Factor-alpha / biosynthesis*
  • Tumor Necrosis Factor-alpha / pharmacology


  • Antigens, Surface
  • Cytokines
  • Interleukin-15
  • Interleukin-2
  • Interleukin-6
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Interferon-gamma
  • Granulocyte-Macrophage Colony-Stimulating Factor