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Differential inhibition of inflammatory cytokine release from cultured alveolar macrophages from smokers and non smokers by No2

Division of Toxicology, Institute of Environmental Medicine, Karolinska Institute, Box 210, S-171 77 Stockholm, Sweden

Ba Tu

Division of Toxicology, Institute of Environmental Medicine, Karolinska Institute, Box 210, S-171 77 Stockholm, Sweden

Anders Blomberg

Department of Lung Medicine, University Hospital of Umeå, S-90185 Umeå, Sweden

Thomas Sandström

Department of Lung Medicine, University Hospital of Umeå, S-90185 Umeå, Sweden

Magnus Sköld

Department of Thoracic Medicine, Karolinska Hospital, S-171 76 Stockholm, Sweden

Anders Eklund

Department of Thoracic Medicine, Karolinska Hospital, S-171 76 Stockholm, Sweden

Ian Cotgreave

Division of Toxicology, Institute of Environmental Medicine, Karolinska Institute, Box 210, S-171 77 Stockholm, Sweden

Human alveolar macrophages (AMs) obtained from smokers and non-smokers by bronchoalveolar lavage (BAL) were subjected to various concentrations of NO₂ in an inverted monolayer exposure model. Culture super natants were collected 4 h after the exposure and assayed for secreted TNF-, IL-1β, IL-8 and MIP-1. The steady state levels of the mRNAs for these cytokines were also analysed in the cells. The adherence of BAL cells to plastic prior to exposure to the gas elevated the steady state mRNA levels of all four cytokines tested in smoker's cells and that of TNF- and IL-1β, but not IL-8 (MIP-1 not tested), in non-smoker's cells. Interestingly, adherent cells from non-smokers released circa 15-, 3-,1.5- and 3-fold the amounts of IL-1β, IL-8, TNF- and MIP-1, respectively, than smoker's cells during control incubation or exposure to air. A 20 min exposure to NO₂ (5 or 20 p.p.m.) did not increase the secretion of any of the cytokines from either cell type. In contrast, NO₂ caused a concentration- dependent inhibition of the secretion of all cytokines except IL-1β from smoker's cells. Additionally, NO₂ greatly diminished the release of all cytokines in response to further treatment with lipopolysaccharide (LPS). In contrast, only the secretion of TNF- from non-smoker's cells was inhibited by the gas in a concentration- dependent manner, whilst LPS-induced secretion of the cytokines was not affected by the gas. The steady state levels of the respective mRNAs for each of the cytokines were not significantly affected in smoker's cells by exposure to NO₂, except for a negative, dose-dependent trend in the case of TNF-. Nitrogen dioxide also failed to elevate the levels of the mRNAs in non-smoker's cells but, again, tended to diminish the levels, particularly of IL-1β mRNA. However, exposure to the gas inhibited LPS- induced accumulation of cytokine mRNAs in smoker's cells only. The data suggest that macrophage-derived cytokine mediators of the sepsis response may not play a role in the generation of NO₂-induced inflammation in the human lung. Conversely, the gas seems to non-specifically inhibit the release and/or production of cytokines, particularly from smoker's cells, at the post-transcrip tional level, and impairs the ability of the cells to increase the transcription and release of the cytokines in response to bacterial LPS. The fact that NO₂ seriously impaired the already diminished capacity of smoker's cells to release several important pro-inflammatory cytokines, both under control conditions and in response to LPS, strongly suggest that the inhalation of NO₂ in cigarette smoke may contribute to impairing host defence against infection in the lung.

Key Words: nitrogen dioxide • alveolar macrophage • cytokine release • gene-expression • smoking

Human & Experimental Toxicology, Vol. 16, No. 10, 577-588 (1997)
DOI: 10.1177/096032719701601005


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