GM-CSF expression in pulmonary epithelial cells is regulated negatively by posttranscriptional mechanisms.
Incubation of pulmonary A549 cells with D609, a phosphatidyl-choline specific phospholipase C (PC-PLC)-inhibitor, or the anti-oxidant, pyrrolidine dithiocarbamate (PTDC), markedly increased IL-1beta-induced GM-CSF elaboration. This effect was observed at the mRNA level and could be partially reproduced by the protein synthesis inhibitor, cycloheximide. Following the peak in GM-CSF mRNA, the mRNA half-life (t(1/2)) was 0.5-1 h. This was increased to around 3 h by cycloheximide, whilst following D609 or PDTC treatment there was essentially no degradation. These data suggest the existence of inhibitory pathways that posttranscriptionally regulate GM-CSF expression via new protein synthesis and D609- and PDTC-sensitive steps. These observations may have important clinical implications. First, drugs that target gene induction may also knock out these inhibitory pathways to lessen their effect. Second, defects in such pathways could lead to overexpression of cytokines or growth factors and contribute to the pathogenesis of inflammatory or proliferative diseases.
Newton
R
R
Thoracic Medicine, National Heart and lung Institute, Imperial College School of Medicine, London, SW3 6LY, United Kingdom. robert.newton@ic.ac.uk
Staples
K J
KJ
Hart
L
L
Barnes
P J
PJ
Bergmann
M W
MW
D000975:Antioxidants / Q000494:pharmacology; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000187:drug effects / Q000502:physiology; D009636:Norbornanes; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D020871:RNA Stability; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism; D013859:Thiocarbamates / Q000494:pharmacology; D013871:Thiones / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D000975:Antioxidants; D001952:Bridged-Ring Compounds; D016328:NF-kappa B; D009636:Norbornanes; D010726:Phosphodiesterase Inhibitors; D011500:Protein Synthesis Inhibitors; D011759:Pyrrolidines; D012333:RNA, Messenger; D013859:Thiocarbamates; D013871:Thiones; C020972:pyrrolidine dithiocarbamic acid; C046498:tricyclodecane-9-yl-xanthogenate; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003513:Cycloheximide