Molecular aspects of glucocorticoid hormone action in rheumatoid arthritis.
Glucocorticoids (GC) are the most powerful anti-inflammatory drugs used in the treatment of autoimmune diseases such as rheumatoid arthritis. In addition, endogenous GC are involved in numerous physiological processes. Most of their effects are mediated by the glucocorticoid receptor (GR) via activation or repression of gene expression. Whereas activation requires DNA binding of the receptor, repression is mediated by protein-protein interactions with other transcription factors. In particular, most immunosuppressive and anti-inflammatory effects are exerted by an interaction of GR with the activating protein 1 (AP-1) and nuclear factor kappaB (NF-kappaB) families of transcription factors without DNA binding. Cytokines such as tumor necrosis factor alpha (TNF-alpha) and interleukin 1 (IL-1) activate the hypothalamus pituitary adrenal (HPA) axis, whereas GC inhibit IL-1 and TNF-alpha forming a cytokine-HPA axis feedback circuit. The high effectiveness of cytokine-antagonists blocking TNF-alpha or IL-1 in RA and the understanding of the precise molecular mechanisms of GC function will enhance our understanding of autoimmune diseases, such as RA, and could suggest new beneficial therapeutic approaches with fewer side-effects.
Neeck
Gunther
G
Department of Internal Medicine, Center of Rheumatology, Rostock Clinic South, Rostock, Germany. gunther.neeck@kliniksued-rostock.de
Renkawitz
Rainer
R
Eggert
Martin
M
D000311:Adrenal Glands / Q000502:physiology; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000628:therapy*; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D007031:Hypothalamus / Q000502:physiology; D007375:Interleukin-1 / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D010902:Pituitary Gland / Q000502:physiology; D011485:Protein Binding; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016207:Cytokines; D005938:Glucocorticoids; D007375:Interleukin-1; D016328:NF-kappa B; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D004247:DNA