title: Endogenous inhibitory cytokines repress TNFalpha secretion.
abstract: Tumor necrosis factor alpha (TNFalpha), with the potential to destroy tissue, is likely to be tightly regulated. A major regulatory step is the translational repression of TNFalpha. 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 TGFbeta, each population released large amounts of TNFalpha, 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 TNFalpha proved to involve both pathways while monocytes were dependent on p38 but not ERK. Changes in soluble TNF receptor levels or cell uptake of TNFalpha were not involved. This study shows that low TNFalpha secretion by resting T-cells and monocytes is maintained by endogenous inhibitors that suppress post-translational processing of TNFalpha by MAP kinases. Keeping TNFalpha levels low is critical to the non-inflammatory steady-state.
authors.affiliation: UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ, USA. jeydels@comcast.net
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Ebert
mesh_terms: D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009500:Neutralization Tests; D011499:Protein Processing, Post-Translational; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism; D012261:Ribonucleoproteins; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D016207:Cytokines; C508609:IL10 protein, human; C508598:IL4 protein, human; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D012261:Ribonucleoproteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C026452:messenger ribonucleoprotein; D016753:Interleukin-10; D015847:Interleukin-4; D048049:Extracellular Signal-Regulated MAP Kinases