TIMP-3: a novel target for glucocorticoid signaling at the blood-brain barrier.
Glucocorticoids (GCs) are used in the treatment of neuroinflammatory diseases such as multiple sclerosis. Several studies have demonstrated the beneficial effect of GCs on the balance between matrix metalloproteinases (MMPs) and their endogenous inhibitors, the TIMPs (tissue inhibitors of metalloproteinases). We could demonstrate that all four known TIMPs are present at the blood-brain barrier (BBB) endothelium. Hydrocortisone (HC) selectively upregulates TIMP-3 while TIMP-1, TIMP-2 and TIMP-4 were downregulated on the mRNA-level. This effect could be completely reversed by the glucocorticoid receptor inhibitor mifepristone (Mife). On the protein-level all TIMPs could be detected in the apical supernatants whereas in the isolated extracellular matrix (ECM) only TIMP-3 was found. The application of HC led to a strong enrichment of TIMP-3 in the ECM. Our findings demonstrate that HC directly targets TIMP-3 at the BBB assuming a protective role against matrix disruption and thus to guarantee the barrier integrity.
Hartmann
Christoph
C
Institute for Biochemistry, Westfaelische Wilhelms-Universitaet Muenster, Wilhelm-Klemm Str. 2, D-48149 Muenster, Germany.
El-Gindi
Jehad
J
Lohmann
Christina
C
Lischper
Mira
M
Zeni
Patrick
P
Galla
Hans-Joachim
HJ
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology; D006854:Hydrocortisone / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000096:biosynthesis* / Q000235:genetics
D005938:Glucocorticoids; D019717:Tissue Inhibitor of Metalloproteinase-3; D006854:Hydrocortisone