Modification of NF-kappa B dependent Interleukin-8 expression via inhibition of histone deacetylation in human alveolar macrophages - effect of cigarette smoking
A. Koch, M. Heimann, M. P. Gaczkowski, K. Wassermann, E. Erdmann (Cologne, Germany)
Source: Annual Congress 2002 - Cell biology and genetics of COPD and emphysema
Session: Cell biology and genetics of COPD and emphysema
Session type: Thematic Poster Session
Number: 632
Disease area: Airway diseases
Abstract The inflammatory cytokine interleukin-8 (IL-8) is implicated in chronic inflammatory airway diseases such as COPD to activate neutrophils and T-lymphocytes. IL-8 release from alveolar macrophages (AM) is primarily regulated at the level of gene transcription by transcription factors such as NF-κB and possibly by modification of histones. Histone deacetylation is associated with gene silencing or transcriptional repression. In this study we investigated the role of NF-kB and histone deacetylation on IL-8 release in AM and compared smokers (S) and non-smokers (NS). LPS (10 ng/ml) induced an increase in IL-8 release (ELISA) in S and NS which was significantly higher in S (p<0.05). SN 50, an inhibitor of NF-kB, reduced IL-8 release by ~60 % in S and NS, indicating that NF-kB is involved in IL-8 expression. In the presence of TSA (10 ng/ml), an inhibitor of histone deacetylase (HDAC), there was an increase in LPS-induced IL-8 release in S and NS, which was significantly higher in S (p<0.05, n=8)compared to NS (n=9). In the presence of LPS (10 ng/ml) SN50-induced inhibition of IL-8 expression was significantly reversed by TSA in S (~41 %, p<0.05)in contrast to NS (~10 %, p>0.05). To study the involvement of mitogen-activated protein kinases p38MAPK and MKK-1 in this process, we used PD 098050 (10 μM), an inhibitor of MKK-1 and SB 203580 (10 μM), an inhibitor of the p38MAPK. PD 098059 decreased LPS-induced IL-8 release in S by 30 % and in NS by 17 %. In the presence of TSA there was a signifcant increase in PD 098059-induced inhibition of IL-8 release by 20 % (p<0.05)in S but only 5 % in NS (p>0.05)and in SB 203580-induced decrease in IL-8 release by 30 % in S (p<0.05)and 15 % in NS (p>0.05). The increased IL-8 release in S may be explained in part by a lower inhibition of HDAC induced by cigarette smoke.
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A. Koch, M. Heimann, M. P. Gaczkowski, K. Wassermann, E. Erdmann (Cologne, Germany). Modification of NF-kappa B dependent Interleukin-8 expression via inhibition of histone deacetylation in human alveolar macrophages - effect of cigarette smoking. Eur Respir J 2002; 20: Suppl. 38, 632
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