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 associated with persistent up-regulation of several "proinflammatory" genes, which are commonly regulated by nuclear factor kappa-B (NF-kappa B). Transcription 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 feedback loop in transient inflammation. To investigate this mechanism in particle inflammation, we have studied I kappa B alpha degradation in A549 cells exposed to DQ12-quartz or TiO2, in relation to the expression of IL-8. Although 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 alpha mRNA-expression compared to quartz, whereas the early enhancement of IL-8 expression and release was similar for both particles. Up-regulation of IL-8 expression was found to persist with quartz only. Cotreatment with PDTC and curcumin reduced particle-elicited IL-8 response, whereas cycloheximide caused enhancement of IL-8 mRNA expression in both the quartz- and TiO2-treated cells. Our results demonstrate that mineral dusts cause I kappa B alpha degradation, a transient increase in de novo synthesis of I kappa B alpha, 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 particle phenomena, particle-specific characteristics impact on activation of I kappa B alpha gene transcription, apparently accounting for the different proinflammatory IL-8 responses seen with quartz and TiO2 in the longer term. 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.