[The mechanism of glucocorticoid resistance in multiple sclerosis].
Glucocorticoids (GCs) are used in the treatment of multiple sclerosis (MS) and other autoimmunological diseases due to their significant anti-inflammatory and immunosuppressive effects. In MS, GCs are mainly used in the treatment of clinical relapses. Most patients benefit from GCs, except for some who are resistant. These patients pose a serious clinical problem. GC resistance in MS has not been widely elaborated. Less than 5% of MS patients do not respond to GCs in the early phase of the disease, and these are considered as having primary resistance to GCs. There is also a group of patients who develop GC resistance later, after a good therapeutic response at the beginning of therapy. This secondary type of resistance is more common and may apply to as many as 30% of all patients. Primary GC resistance has a genetic origin and is associated with a mutation within the GR. The mechanisms of secondary GC resistance are more diverse. There is only one receptor for GCs, but it can occur in three isoforms: GR alpha, GR beta, and GR gamma. GR alpha secures the appropriate GC signaling transmission, whereas GR beta and gamma bind to GC, but prevent the GC/GR complex from DNA activation. Thus both these latter forms of GR inhibit GC activity. The beta and gamma isoforms of GR become more common in cells at the inflammatory foci. Another mechanism of secondary GC resistance depends on the induction of cytokines during inflammatory processes. Interleukins 2, 4, and 13 are overproduced and lead to the induction of transcriptional factor AP-1. AP-1 competes with the GC/GR complex for the binding site on DNA. In addition, IL-2 slows the transport of the GC/GR complex to cell nuclei. In assessing GC resistance it is important to consider additional factors, such as patient compliance with the treatment.
Rzazewska-Makosa
Beata
B
Klinika Neurologii Uniwersytetu Medycznego, 90-153 Łódź. beata.rzazewska@schering.de
D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004351:Drug Resistance / Q000235:genetics; D005938:Glucocorticoids / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology; D011965:Receptors, Glucocorticoid / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D011965:Receptors, Glucocorticoid