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Endogenous inhibitory cytokines repress TNFalpha secretion

Ellen C Ebert1

  • 1UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ, USA. jeydels@comcast.net

Cellular Immunology
|January 3, 2006
PubMed

Insights

Endogenous inhibitory cytokines suppress tumor necrosis factor alpha (TNFalpha) production by monocytes and T-cells. This post-translational regulation by MAP kinases maintains low TNFalpha levels, crucial for a non-inflammatory state.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Tumor necrosis factor alpha (TNFalpha) is a potent cytokine with significant tissue-damaging potential, necessitating tight regulation.
  • Translational repression is a key mechanism controlling TNFalpha levels, but the role of endogenous inhibitory cytokines remains unclear.

Purpose of the Study:

  • To investigate whether endogenous inhibitory cytokines contribute to the translational repression of TNFalpha.
  • To elucidate the post-translational regulatory mechanisms controlling TNFalpha release from monocytes and T-cells.

Main Methods:

  • Isolation of primary human monocytes and T-cells/NK-cells from peripheral blood with minimal activation.
  • Culture of cells with neutralizing antibodies against IL-4, IL-10, and TGF-beta, or with inhibitors of p38 MAP kinase and ERK.
  • Measurement of TNFalpha release and transcript levels, and assessment of protein/RNA synthesis inhibition.

Main Results:

  • Neutralization of IL-4, IL-10, or TGF-beta induced significant TNFalpha release from both monocytes and T-cells, without altering transcript levels.
  • T-cell TNFalpha release involved both p38 MAP kinase and ERK pathways, while monocyte release was dependent on p38 MAP kinase only.
  • Inhibitors of protein or RNA synthesis did not affect TNFalpha release, indicating post-translational regulation.

Conclusions:

  • Endogenous inhibitory cytokines maintain low TNFalpha secretion in resting T-cells and monocytes.
  • This suppression occurs at the post-translational level, mediated by MAP kinase pathways.
  • Maintaining low TNFalpha levels is essential for the non-inflammatory steady-state.

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