Non-steroidal anti-inflammatory drugs inhibit the expression of cytokines and induce HSP70 in human monocytes

Recent studies have shown that the non-steroidal anti-inflammatory drugs (N SAIDs) activate heat shock transcription factor (HSF1) from a latent cytopl asmic form to a nuclear, DNA binding state. As HSF1 can function as both an activator of heat shock genes and a repressor of non-heat shock genes such as IL1B and c-fos, we have examined the potential role of HSF1 in the effe cts of NSAIDs on gene expression in a human monocytic cell line THP-1. We f ound that two members of the NSAIDs, sodium salicylate and sulindac repress the IL1B promoter to similar degree to heat shock or HSF1 overexpression. In addition, sodium salicylate and additional NSAIDs used at concentrations that activate HSF1 also inhibited the expression of other monocytic genes (TNF-alpha, IL-1 beta, IL-6, IL-8, IL-10, ICAM-1) activated by exposure to a pro-inflammatory stimulus (lipopolysaccharide, LPS). At least in the case of the IL1B promoter, repression did not seem to involve another factor wh ose activity is affected by the NSAIDs, NF kappa B as the IL1B promoter fra gment used in our studies is not NF kappa B responsive and binds specifical ly to HSF1, Exposure to NSAIDs had a complex effect on HSP gene expression and while sulindac activated the stress responsive HSP70B promoter, sodium salicylate did not. In addition, only a subset of the NSAIDs induced HSP70 mRNA species. These findings reflect the properties of HSF1 which can be ac tivated to at least two DNA binding forms only one of which activates heat shock promoters and suggest that individual NSAID family members may differ entially induce one or other of these forms. Overall therefore, exposure to NSALDs leads to a profound switch in gene expression in monocytic cells, w ith suppression of genes involved in macrophage activation and induction of stress genes and HSF1 appears to play a regulatory role in these effects. (C) 1999 Academic Press.