TIMP-3: A novel target for glucocorticoid signaling at the blood-brain barrier

Christoph Hartmann, Jehad El-Gindi, Christina Lohmann, Mira Lischper, Patrick Zeni, Hans Joachim Galla

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)182-186
Number of pages5
JournalBiochemical and Biophysical Research Communications
Volume390
Issue number2
DOIs
StatePublished - 11 Dec 2009
Externally publishedYes

Keywords

  • Blood-brain barrier
  • Extracellular matrix
  • Hydrocortisone
  • Tissue inhibitor of metalloproteinases

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