Targets of glucocorticoid action on TNF-alpha release by macrophages.
Glucocorticoid drugs affect virtually every cell type involved in inflammatory response, to some degree. Macrophage/monocytes (Mphi) are particularly sensitive, and glucocorticoids suppress release of most known Mphi inflammatory mediators, including TNF-alpha. In the case of TNF-alpha, several levels of regulation are already characterised and ongoing research hints at further glucocorticoid targets. The relative importance of transcriptional and post-transcriptional regulation is lineage-dependent and may also change during the course of Mphi differentiation. In human monocytic cell lines, glucocorticoids primarily suppress transcriptional activation through adjacent promoter binding sites for NF-kappaB transcription factor complexes and for complexes of c-Jun with activating transcription factor-2 (ATF-2). The goal of glucocorticoid research in inflammation is to develop drugs with the anti-inflammatory potential of glucocorticoids, but without the systemic toxicity. Each of the multiple targets for glucocorticoid action presents an opportunity for anti-inflammatory drug development. However, none of the known targets is unique to Mphi, and no single pathway is preeminent in all situations. Research is now directed at characterising targets and regulating them without systemic activation of the glucocorticoid receptor.
Joyce
D A
DA
Department of Pharmacology, University of Western Australia, Nedlands, Australia. djoyce@receptor.pharm.uwa.edu.au
Gimblett
G
G
Steer
J H
JH
D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism*
D005938:Glucocorticoids; D014409:Tumor Necrosis Factor-alpha