Reduced cortisol levels in cerebrospinal fluid and differential distribution of 11beta-hydroxysteroid dehydrogenases in multiple sclerosis: implications for lesion pathogenesis.
Relapses during multiple sclerosis (MS) are treated by administration of exogenous corticosteroids. However, little is known about the bioavailability of endogenous steroids in the central nervous system (CNS) of MS patients. We thus determined cortisol and dehydroepiandrosterone (DHEA) levels in serum and cerebrospinal fluid (CSF) samples from 34 MS patients, 28 patients with non-inflammatory neurological diseases (NIND) and 16 patients with other inflammatory neurological diseases (OIND). This revealed that MS patients - in sharp contrast to patients with OIND - show normal cortisol concentrations in serum and lowered cortisol levels in the CSF during acute relapses. This local cortisol deficit may relate to poor local activation of cortisone via 11beta-hydroxysteroid dehydrogenase type 1 (11bHSD1) or to inactivation via 11bHSD2. Accordingly, 11bHSD2 was found to be expressed within active plaques, whereas 11bHSD1 was predominantly detected in surrounding "foamy" macrophages. Our study thus provides new insights into the impaired endogenous CNS cortisol regulation in MS patients and its possible relation to MS lesion pathogenesis. Moreover, an observed upregulation of 11bHSD1 in myelin-loaded macrophages in vitro suggests an intriguing hypothesis for the self-limiting nature of MS lesion development. Finally, our findings provide an attractive explanation for the effectivity of high- vs. low-dose exogenous corticosteroids in the therapy of acute relapses.
Heidbrink
Claudia
C
Department for Obstetrics and Gynecology, University of Würzburg, Würzburg, Germany.
Häusler
Sebastian F M
SF
Buttmann
Mathias
M
Ossadnik
Monika
M
Strik
Herwig M
HM
Keller
Andreas
A
Buck
Dorothea
D
Verbraak
Evert
E
van Meurs
Marjan
M
Krockenberger
Mathias
M
Mehling
Matthias
M
Mittelbronn
Michel
M
Laman
Jon D
JD
Wiendl
Heinz
H
Wischhusen
Jörg
J
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000096:biosynthesis / Q000134:cerebrospinal fluid; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000096:biosynthesis / Q000134:cerebrospinal fluid; D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000134:cerebrospinal fluid*; D000328:Adult; D001921:Brain / Q000201:enzymology; D002452:Cell Count; D003687:Dehydroepiandrosterone / Q000097:blood / Q000134:cerebrospinal fluid; D005260:Female; D005487:Foam Cells / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000134:cerebrospinal fluid*; D007150:Immunohistochemistry; D008264:Macrophages / Q000201:enzymology; D008297:Male; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid* / Q000201:enzymology / Q000473:pathology*; D009185:Myelin Proteins / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D009185:Myelin Proteins; D003687:Dehydroepiandrosterone; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D042842:11-beta-Hydroxysteroid Dehydrogenases; D006854:Hydrocortisone