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.

journal_name

Biochem Pharmacol

journal_title

Biochemical pharmacology

authors

Sarir H,Mortaz E,Janse WT,Givi ME,Nijkamp FP,Folkerts G

doi

10.1016/j.bcp.2009.10.001

subject

Has Abstract

pub_date

2010-03-01 00:00:00

pages

698-705

issue

5

eissn

0006-2952

issn

1873-2968

pii

S0006-2952(09)00853-3

journal_volume

79

pub_type

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