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Regulation of LPS-mediated inflammation in vivo and in vitro by the thiol antioxidant Nacystelyn

¹Edinburgh Lung and Environment Group Initiative/Colt Research Laboratories, Department of Medical & Radiological Sciences, University of Edinburgh Medical School; and ²School of Life Sciences, Napier University, Edinburgh EH8 9AG, United Kingdom

Submitted 15 September 2003 ; accepted in final form 2 February 2004

Increased levels of proinflammatory cytokines are present in bronchoalveolar lavage fluid in various lung diseases. Redox-sensitive transcription factors such as NF-B regulate gene transcription for these cytokines. We therefore studied the effect of a new thiol antioxidant compound, Nacystelyn (NAL), on IL-8 regulation in a human macrophage-derived cell line (THP-1). LPS (10 µg/ml) increased IL-8 release compared with control levels. This LPS activation was inhibited by coincubation with NAL (1 and 5 mM). Pretreatment with cycloheximide or okadaic acid, protein synthesis, and serine/threonine phosphatase inhibitors, respectively, did not modify inhibition of IL-8 release caused by NAL. NF-B and C/EBP DNA binding were increased after LPS treatment compared with control, an effect inhibited by cotreatment with NAL. Activator protein (AP)-1 DNA binding was unaffected. The enhanced neutrophil chemotaxis produced by conditioned media from LPS-treated cells was inhibited when cells were cotreated with NAL. The selectivity of NAL inhibition upon IL-8 expression was studied. LPS-treated THP-1 cells also had higher levels of TNF-, transforming growth factor (TGF)-1 and -3, MIP-1 and -, and RANTES gene expression. However, only LPS-induced IL-8 and TGF-1 expressions were inhibited by NAL. An anti-inflammatory effect of NAL was confirmed in vivo as shown by a reduction in LPS-induced neutrophil recruitment to the lungs following instillation of NAL into the lungs. Our studies demonstrate that NAL has anti-inflammatory properties in vitro and in vivo, may therefore have a therapeutic role in lung inflammation, and has the advantage over other antioxidant agents in that it may be administrated by inhalation.

interleukin-8; lipopolysaccharide; THP-1 cells

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