Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have shown that the non-steroidal anti-inflammatory drugs (NSAIDs) activate heat shock transcription factor (HSF1) from a latent cytoplasmic 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 effects of NSAIDs on gene expression in a human monocytic cell line THP-1. We found 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-1beta, 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 whose activity is affected by the NSAIDs, NFkappaB as the IL1B promoter fragment used in our studies is not NFkappaB responsive and binds specifically 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 activated to at least two DNA binding forms only one of which activates heat shock promoters and suggest that individual NSAID family members may differentially induce one or other of these forms. Overall therefore, exposure to NSAIDs leads to a profound switch in gene expression in monocytic cells, with suppression of genes involved in macrophage activation and induction of stress genes and HSF1 appears to play a regulatory role in these effects.
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PMID:Non-steroidal anti-inflammatory drugs inhibit the expression of cytokines and induce HSP70 in human monocytes. 1032 74

We have examined the functional antagonism between the regulator of the heat shock response, HSF1, and NF-IL6, which plays a major role in control of the acute phase response (APR). Agents that activate HSF1 such as heat shock and sodium salicylate inhibit NF-IL6 induced transcription while NF-IL6 activators such as lipopolysaccharide (LPS) and interleukin 6 (IL-6) repressed the stress responsive HSP70B promoter. In transfection studies, the inhibitory effects of HSF1 and NF-IL6 on the c-fms promoter were shown to be highly dose-dependent. Furthermore, heat shock is inhibitory to differentiation-linked expression of macrophage colony stimulating factor (M-CSF) receptor, product of the c-fms gene, which is transcriptionally activated by NF-IL6 but repressed by HSF1. Our studies suggest a strong mutual antagonism between the heat shock response and APR, which may influence the sensitivity and duration of inflammatory responses.
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PMID:NF-IL6 and HSF1 have mutually antagonistic effects on transcription in monocytic cells. 1186 74