Negative role of cAMP-dependent protein kinase A in RANTES-mediated transcription of proinflammatory mediators through Raf.
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.
Zhang
Ye
Y
Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Luo
Yi
Y
Zhai
Qiwei
Q
Ma
Liying
L
Dorf
Martin E
ME
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018946:Chemokine CCL5 / Q000494:pharmacology*; D018925:Chemokines / Q000235:genetics* / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology*; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D037342:Pertussis Toxin / Q000494:pharmacology; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
D018946:Chemokine CCL5; D018925:Chemokines; D016207:Cytokines; D012333:RNA, Messenger; D005576:Colforsin; D000242:Cyclic AMP; D037342:Pertussis Toxin; D019908:Proto-Oncogene Proteins c-raf; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases