title: 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.affiliation: Division of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Sciences, Utrecht University, P.O. Box 80082, 3508 TB Utrecht, The Netherlands.
authors.forename: Hadi
authors.initials: H
authors.lastname: Sarir
authors.forename: Esmaeil
authors.initials: E
authors.lastname: Mortaz
authors.forename: Willem T
authors.initials: WT
authors.lastname: Janse
authors.forename: Masoumeh E
authors.initials: ME
authors.lastname: Givi
authors.forename: Frans P
authors.initials: FP
authors.lastname: Nijkamp
authors.forename: Gert
authors.initials: G
authors.lastname: Folkerts
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004338:Drug Combinations; D004357:Drug Synergism; D004646:Emphysema / Q000188:drug therapy / Q000378:metabolism; D005978:Glutathione; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D016328:NF-kappa B / Q000096:biosynthesis; D020030:Nitric Oxide Donors / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012906:Smoke / Q000009:adverse effects*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000975:Antioxidants; D004338:Drug Combinations; D016209:Interleukin-8; D016328:NF-kappa B; D020030:Nitric Oxide Donors; D017382:Reactive Oxygen Species; D012906:Smoke; D014409:Tumor Necrosis Factor-alpha; C002385:linsidomine; D008981:Molsidomine; D005978:Glutathione