Sesquiterpene lactones are potent inhibitors of interleukin 8 gene expression in cultured human respiratory epithelium.
Sesquiterpene lactones, derived from Mexican-Indian medicinal plants, are known to have potent anti-inflammatory properties but the mechanisms of this effect are not completely understood. Recent data demonstrated that sesquiterpene lactones were potent inhibitors of the pro-inflammatory transcription factor NF-kappaB. Because activation of NF-kappaB is involved in the regulation of the chemokine interleukin 8 (IL-8), we hypothesized that the sesquiterpene lactones, isohelenin and parthenolide, would inhibit IL-8 gene expression in cultured human respiratory epithelium. Incubating A549 cells with tumour necrosis factor alpha (TNF-alpha) induced IL-8 mRNA expression and secretion of immunoreactive IL-8. Pretreatment with either isohelenin or parthenolide inhibited TNF-alpha-mediated IL-8 gene expression in a concentration-dependent manner. Pretreatment with either compound inhibited TNF-alpha mediated activation of the IL-8 promoter and TNF-alpha-mediated nuclear translocation of NF-kappaB. In addition, pretreatment with isohelenin or parthenolide inhibited TNF-alpha-mediated degradation of the NF-kappaB inhibitory protein, I-kappaBalpha. We conclude that sesquiterpene lactones are potent in vitro inhibitors of IL-8 gene expression in cultured human respiratory epithelium. The most proximal mechanism of inhibition appears to involve inhibition of I-kappaBalpha degradation. Stabilization of cytoplasmic I-kappaBalpha leads to inhibition of NF-kappaB nuclear translocation and of subsequent IL-8 promoter activation. The ability of sesquiterpene lactones to modulate IL-8 gene expression may explain, in part, their anti-inflammatory effects.
Mazor
R L
RL
Divisions of Critical Care Medicine and Pulmonary Medicine, Children's Hospital Research Foundation, Cincinnati, Ohio, USA.
Menendez
I Y
IY
Ryan
M A
MA
Fiedler
M A
MA
Wong
H R
HR
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001692:Biological Transport; D004268:DNA-Binding Proteins / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D020672:I-kappa B Proteins; D016209:Interleukin-8 / Q000235:genetics*; D008168:Lung / Q000166:cytology / Q000276:immunology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010946:Plants, Medicinal / Q000737:chemistry*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016209:Interleukin-8; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D012333:RNA, Messenger; D012717:Sesquiterpenes; D014409:Tumor Necrosis Factor-alpha; C103906:isohelenin; D000072000:NF-KappaB Inhibitor alpha; C002669:parthenolide