Some antioxidants inhibit, in a co-ordinate fashion, the production of tumor necrosis factor-α, IL-β, and IL-6 by human peripheral blood mononuclear cells

Abstract

Some antioxidants, including butylated hydroxyanisole (BHA), tetrahydropapaveroline (THP), nordihydroguiauretic acid, and 10,11-dihydroxyaporphine (DHA), were found to be potent inhibitors of the production of tumor necrosis factor (TNF)-alpha, IL-1 beta, and IL-6 by human peripheral blood mononuclear cells (PBMC) stimulated by lipopolysaccharide (LPS) (IC50s in the low micromolar range). Inhibition of cytokine production was gene selective and not due to general effects on protein synthesis. Inhibition of cytokine production by PBMC was observed also when other inducers were used (staphylococci, silica, zymosan). Much higher concentrations of other antioxidants--including ascorbic acid, trolox, alpha-tocopherol, butylated hydroxytoluene, and the 5-lipoxygenase inhibitor zileuton--did not affect the production of these cytokines. The active compounds did not inhibit IL-1-induced production of IL-6 in fibroblasts, showing the cell selectivity of the effect. Antioxidant-mediated inhibition of cytokine production was correlated with low levels of the corresponding messenger RNAs. Nuclear run-on experiments showed that THP inhibited transcription of the IL-1 beta gene. THP decreased the concentration of the transcription factors NF-kappa B and AP-1 detected in nuclear extracts of PBMC cultured in the presence or absence of LPS. THP and DHA markedly decreased the levels of TNF-alpha and IL-1 beta in the circulation of mice following LPS injection. Thus antioxidants vary widely in potency as inhibitors of the activation of transcription factors and of the transcription of genes for pro-inflammatory cytokines. Coordinate inhibition of the transcription of genes for inflammatory cytokines could provide a strategy for therapy of diseases with inflammatory pathogenesis and for septic shock.

Mechanisms of Dimethyl Sulfoxide Augmentation of IL-1β Production

“…Substantial evidence exists supporting the concept that antioxidants, including synthetic and natural products, suppress cytokine production by monocytes/macrophages (20,32). These previous papers indicate that ROIs play an important role in LPS-induced cytokine production.…”

“…Riboprobe syntheses was driven by the T7 bacteriophage RNA polymerase with [␣-32 P]UTP as the labeling nucleotide. 32 P probe (6 ϫ 10 5 cpm/sample) was added to tubes containing the sample RNA (4 g), which was dissolved in 8 l of hybridization buffer. The samples were heated to 90°C, the temperature slowly decreased to 56°C, and then incubated overnight.…”

“…It has been reported that antioxidant reagents inhibit LPS-induced IL-1␤, TNF-␣, and IL-6 production by monocytes/macrophages (20,32,33). Koga et al (34) reported that hydroxyl free radical scavengers inhibit IL-1␤ production induced by reoxygenation, and that oxygen free radicals are capable of triggering IL-1␤ production by monocytes.…”

A Small Molecule Ubiquitination Inhibitor Blocks NF-κB-dependent Cytokine Expression in Cells and Rats

“…Although Ro106-9920 does have activity against 5-lipoxygenase and inducible nitric-oxide synthase, zileuton, an inhibitor of 5-lipoxygenase, does not inhibit TNF␣ production in PBMNs (40), and endogenous nitric oxide decreases TNF␣ in rat models of hepatic ischemia-reperfusion (41).…”

Hydrogen peroxide as a potent activator of T lymphocyte functions

“…Recent evidence suggests that ROI may be not only part of an antimicrobial defense mechanism but may also be involved in signal transduction of immunoregulatory processes [3,4]. For instance, ROI have been shown to induce the expression of cytokines [5][6][7], adhesion molecules [8,9] and proto-oncogenes [10,11]. We and others have demonstrated that gene expression in response to ROI can be attributed to the activation of certain transcription factors including NF-xB and AP-1, both of which are activated under prooxidant conditions [12][13][14].…”