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Negative role of cAMP‐dependent protein kinase A in RANTES‐mediated transcription of proinflammatory mediators through Raf
Author(s) -
Zhang Ye,
Luo Yi,
Zhai Qiwei,
Ma Liying,
Dorf Martin E.
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0962fje
Subject(s) - proinflammatory cytokine , chemokine , protein kinase a , creb , microbiology and biotechnology , astrocyte , transcription factor , chemistry , biology , kinase , immunology , inflammation , central nervous system , endocrinology , biochemistry , gene
The chemokine RANTES (regulated on activation normal T cell expressed and secreted) is expressed in several inflammatory diseases of the central nervous system and is a powerful stimulus for astrocyte production of proinflammatory mediators. The mechanism of RANTES‐mediated astrocyte activation was investigated. RANTES stimulation decreased both intracellular cyclic AMP (cAMP) levels and cAMP‐dependent protein kinase A (PKA) activity in cultures of primary mouse astrocytes. H‐89, a potent inhibitor of PKA, mimicked RANTES‐mediated chemokine and cytokine transcription. RANTES treatments activated Raf‐1 kinase activity, and conversely a dominant negative Raf and a Raf‐1 inhibitor blocked RANTES‐induced chemokine transcription. Transfection with a constitutively active Raf was sufficient to induce transcription of proinflammatory mediators. The combined data indicate that Raf‐1 is required for RANTES‐mediated astrocyte activation. Decreases of cAMP and PKA activity contributed to the transcription of proinflammatory mediators by cross‐talk with the Raf‐1/mitogen‐activated protein kinase pathway. The results identify an upstream signaling pathway for amplification of proinflammatory mediators in the central nervous system.