Persistent depletion of I kappa B alpha and interleukin-8 expression in human pulmonary epithelial cells exposed to quartz particles

Chronic inflammation and fibrosis following quartz inhalation has been asso ciated with persistent up-regulation of several "proinflammatory" genes, wh ich are commonly regulated by nuclear factor kappa-B (NF-kappa B). Transcri ption of the NF-kappa B-inhibitor I kappa B alpha is also under NF-kappa B control, and its de novo synthesis is considered to comprise a negative fee dback loop in transient inflammation. To investigate this mechanism in part icle inflammation, we have studied I kappa B alpha degradation in A549 cell s exposed to DQ12-quartz or TiO2, in relation to the expression of IL-8. Al though both quartz and TiO2 were found to cause I kappa B alpha degradation , only quartz elicited a mild I kappa B alpha depletion, first appearing at 4 h. TiO2 was found to cause a higher short-term increase in I kappa B alp ha mRNA-expression compared to quartz, whereas the early enhancement of IL- 8 expression and release was similar for both particles. Up-regulation of I L-8 expression was found to persist with quartz only. Cotreatment with PDTC and curcumin reduced particle-elicited IL-8 response, whereas cycloheximid e caused enhancement of IL-8 mRNA expression in both the quartz- and TiO2-t reated cells. Our results demonstrate that mineral dusts cause I kappa B al pha degradation, a transient increase in de novo synthesis of I kappa B alp ha, and enhanced IL-8 expression in human pulmonary epithelial cells. While I kappa B alpha degradation and early IL-8 expression seem to be general p article phenomena, particle-specific characteristics impact on activation o f I kappa B alpha gene transcription, apparently accounting for the differe nt proinflammatory IL-8 responses seen with quartz and TiO2 in the longer t erm. These observations may provide an explanation for the transient versus the persistent pulmonary inflammatory status and subsequent differences in pathogenic potency of TiO2 and quartz. (C) 2000 Academic Press.