Thiol regulation of the production of TNF-α, IL-6 and IL-8 by human alveolar macrophages
Version of Record online: 25 DEC 2001
European Respiratory Journal
Volume 14, Issue 1, pages 98–105, July 1999
How to Cite
Gosset, P. , Wallaert, B. , Tonnel, A.B. and Fourneau, C. (1999), Thiol regulation of the production of TNF-α, IL-6 and IL-8 by human alveolar macrophages. European Respiratory Journal, 14: 98–105. doi: 10.1034/j.1399-3003.1999.14a17.x
- Issue online: 25 DEC 2001
- Version of Record online: 25 DEC 2001
- Alveolar macrophage;
- N-acetylcysteine ;
- tumour necrosis factor
Reactive oxygen intermediates exert signalling functions and modulate gene transcription, particularly for pro-inflammatory cytokines. Since exogenous as well as endogenous thiols could be potent inhibitors of the production of cytokines, the effects of N-acetylcysteine (NAC), glutathione (GSH) and modulated GSH synthesis on the production of tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-8 by human alveolar macrophages (AMs) was evaluated, as well as the potential role of intracellular GSH depletion on the effect of exogenous thiols.
AMs were stimulated with lipopolysaccharide (LPS) and cytokine production was measured by evaluating messenger ribonucleic acid (mRNA) expression and protein secretion.
Depletion of intracellular GSH by treatment with buthionine sulphoximine (BSO) reached 45.2% after 3 h and was nearly complete at 24 h. Whereas a 24-h preincubation of AMs with BSO significantly increased LPS-induced secretion of TNF-α and IL-8, a 3-h preincubation only enhanced LPS-stimulated production of IL-8 (p<0.05). Treatment with NAC and GSH did not significantly increase intracellular content of GSH even after a 48-h incubation. Addition of GSH and NAC significantly reduced the secretion of TNF-α (mean±sem 21.2±5 and 44.7±4.4% inhibition, respectively) as well as LPS-induced IL-6 and IL-8 (p<0.05). Similarly, NAC inhibited the production of TNF-α, IL-6 and IL-8 in GSH-depleted AMs obtained by BSO pretreatment.
In conclusion, N-acetylcysteine and glutathione inhibit the production of tumour necrosis factor-α, interleukin-8 and interleukin-6 by alveolar macrophages by a mechanism independent of glutathione metabolism. However, total depletion of glutathione within alveolar macrophages significantly increases tumour necrosis factor-α and interleukin-8 synthesis whereas it does not modulate interleukin-6 secretion.