Endogenous inhibitory cytokines repress TNFalpha secretion

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.