TGF-β1 represses activation and resultant death of microglia via inhibition of phosphatidylinositol 3-kinase activity

Won Ki Kim, So Young Hwang, Eok Soo Oh, Hua Zi Piao, Ki Wan Kim, Inn Oc Han

Research output: Contribution to journalArticle

90 Citations (Scopus)

Abstract

Overactivation of microglial cells may cause severe brain tissue damage in various neurodegenerative diseases. Therefore, the overactivation of microglia should be repressed by any means. The present study investigated the potential mechanism and signaling pathway for the repressive effect of TGF-β1, a major anti-inflammatory cytokine, on overactivation and resultant death of microglial cells. A bacterial endotoxin LPS stimulated expression of inducible NO synthase (iNOS) and caused death in cultured microglial cells. TGF-β1 markedly blocked these LPS effects. However, the LPS-evoked death of microglial cells was not solely attributed to excess production of NO. Because phosphatidylinositol 3-kinase (PI3K) was previously shown to play a crucial role in iNOS expression and cell survival signals, we further studied whether PI3K signaling was associated with the suppressive effect of TGF-β1. Like TGF-β1, the PI3K inhibitor LY294002 blocked iNOS expression and death in cultured microglial cells. Both TGF-β1 and LY294002 decreased the activation of caspases 3 and 11 and the mRNA expression of various kinds of inflammatory molecules caused by LPS. TGF-β1 was further found to decrease LPS-induced activation of PI3K and Akt. TGF-β1 and LY294002 suppressed LPS-induced p38 mitogen-activated kinase and c-Jun N-terminal kinase activity. In contrast, TGF-β1 and LY294002 enhanced LPS-induced NF-κB activity. Our data indicate that TGF-β1 protect normal or damaged brain tissue by repressing overactivation of microglial cells via inhibition of PI3K and its downstream signaling molecules.

Original languageEnglish
Pages (from-to)7015-7023
Number of pages9
JournalJournal of Immunology
Volume172
Issue number11
DOIs
Publication statusPublished - 2004 Jun 1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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