Endogenous inhibitory cytokines repress TNFα secretion

Tumor necrosis factor α (TNFα), with the potential to destroy tissue, is likely to be tightly regulated. A major regulatory step is the translational repression of TNFα. This study evaluates whether endogenous inhibitory cytokines account for this repression. Two cell populations were isolated from peripheral blood using techniques that minimized activation, one composed primarily of monocytes and the other containing T-cells and NK-cells. When cultured without a stimulus in the presence of Abs neutralizing IL-4, IL-10, or TGFβ, each population released large amounts of TNFα, reaching levels induced by PHA or LPS. Their actions were at the post-translational level since the numbers of transcripts did not change, and inhibitors of protein or RNA synthesis had no effects. When inhibitors of 38 MAP kinase and ERK were added, T-cell release of TNFα proved to involve both pathways while monocytes were dependent on p38 but not ERK. Changes in soluble TNF receptor levels or cell uptake of TNFα were not involved. This study shows that low TNFα secretion by resting T-cells and monocytes is maintained by endogenous inhibitors that suppress post-translational processing of TNFα by MAP kinases. Keeping TNFα levels low is critical to the non-inflammatory steady-state.