IL-8 production by macrophages is synergistically enhanced when cigarette smoke is combined with TNF-alpha.

Abstract

Macrophages are key inflammatory cells in chronic obstructive pulmonary disease (COPD). The pathophysiology of cigarette smoke-induced lung emphysema is complex but there is a clear role for reactive oxygen species (ROS, such as peroxynitrite), tumor necrosis factor (TNF-alpha) and interleukin (IL)-8. We investigated whether TNF-alpha or cigarette smoke medium (CSM) alone or in combination induces the production of IL-8 by human macrophages or monocyte lymphoma U937. CSM and TNF-alpha induce a dose- and time-dependent increase in IL-8 production. Interestingly, when sub-threshold concentrations of CSM and TNF-alpha were co-incubated, a 1500% increase in IL-8 production was observed compared to either of the compounds alone. Similar results were obtained with TNF-alpha and the peroxynitrite donor SIN-1. Moreover, the overproduction of IL-8 was associated with an enhanced increase in the translocation of NF-kappaB and an enhanced decrease in glutathione levels. Preincubation of the cells with antioxidants, such as N-acetyl-L-cysteine (NAC), prevented the overproduction of IL-8 and activation of NF-kappaB. In conclusion, CSM exposure of macrophages up-regulates the expression and the production of IL-8 via reactive oxygen species and NF-kappaB activation. Moreover, CSM dramatically enhances the production of IL-8 in combination with TNF-alpha. Based upon the strong synergistic action, a combination therapy directed against ROS and TNF-alpha could be a new approach to stop the progression in lung damage during emphysema.

• Authors: Hadi Sarir, Esmaeil Mortaz, Willem T Janse, Masoumeh E Givi, Frans P Nijkamp, Gert Folkerts
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 79 Issue 5 Pg. 698-705 (Mar 01 2010) ISSN: 1873-2968 [Electronic] England
• PMID: 19874800 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: 2009 Elsevier Inc. All rights reserved.

Chemical References

• Antioxidants
• Drug Combinations
• Interleukin-8
• NF-kappa B
• Nitric Oxide Donors
• Reactive Oxygen Species
• Smoke
• Tumor Necrosis Factor-alpha
• linsidomine
• Molsidomine
• Glutathione

Topics

• Antioxidants (pharmacology)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Drug Antagonism
• Drug Combinations
• Drug Synergism
• Emphysema (drug therapy, metabolism)
• Glutathione
• Humans
• Interleukin-8 (metabolism)
• Macrophages (drug effects, metabolism)
• Molsidomine (analogs & derivatives, pharmacology)
• NF-kappa B (biosynthesis)
• Nitric Oxide Donors (pharmacology)
• Reactive Oxygen Species (metabolism)
• Smoke (adverse effects)
• Time Factors
• Tumor Necrosis Factor-alpha (pharmacology)
• Up-Regulation (drug effects)