Modulation of NF-KappaB and cytokine responses in lung cells by pro-oxidant and antioxidant agents.
Ufferfilge-D; Cosma-G; Martinez-A; Gardner-H; Vallyathan-V
Toxicologist 1998 Mar; 42(1-S):346
Previous studies from our laboratory have indicated a central role for oxygen free radicals in lung pathogenesis following exposures to particulates. Current studies are investigating the modulation of DNA binding of transcription factor NF-kappaB by pro-oxidant and antioxidant agents, and the activities of proinftammatory cytokines interleukin-1/6, and TNF-alpha. Stimulation of rat alveolar macrophage NR8383 and human monocytic THP-l cell lines with organic particulates resulted in a ten-fold increase in NF-kappaB activity, as determined by electrophoretic mobility shift assay, by 45 min post-treatment which coincided with the production of hydrogen peroxide. IL-l and TNF-alpha levels, as detected by ELISA, increased by 6 hr, and IL-6 levels rose by 24 hr. Pre-treatments of cells with 20 mM n-acetylcysteine, previously shown to significantly inhibit hydrogen peroxide fomtation and cytokinc production in macrophages, did not result in inhibition of NF-kappaB activity in stimulated THP-I cells. The pineal hormone melatonin also did not appear to modulate DNA binding of NF-kappaB protein, despite a modest inhibition of hydrogen peroxide formation in cells. Interestingly, melatonin treated cells displayed a biphasic dose-response of synthesis of pro-inflammatory cytokines. Ongoing studies are further investigating the effects of melatonin on transcription factor activities and stress protein responses in lung cells, and its relationship to quenching of reactive oxygen species as detected by electron spin resonance.
Free-radicals; Free-radical-generation; Lung-function; Lung-irritants; Lung-disease; Lung-burden; Lung-tissue; Particulates; Particulate-sampling-methods; Antioxidants; Antioxidation
The Toxicologist. Society of Toxicology 37th Annual Meeting, March 1-5,1998, Seattle, Washington