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-kappa B. Because activation of NF-kappa B 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-a mediated activation of the IL-8 promoter and TNF-alpha-mediated nuclear translocation of NF-kappa B, In addition, pretreatment with isohelenin or parthenolide inhibited TNF-alpha-mediated degradation of the NF-kappa B inhibitory protein, I-kappa B alpha, 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-kappa B alpha degradation. Stabilization of cytoplasmic I-kappa B alpha leads to inhibition of NF-kappa B 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. (C) 2000 Academic Press.