RANTES-mediated chemokine transcription in astrocytes involves activation and translocation of p90 ribosomal S6 protein kinase (RSK).
RANTES (regulated on activation normal T cell expressed and secreted) (> or =10 ng/ml) stimulates the induction of KC and other chemokines in astrocytes. Elements of the signal transduction pathway controlling this response were identified. RANTES induced phosphorylation of MEK, ERK1/2, p90 ribosomal S6 kinases (RSK), and cAMP-response element-binding protein (CREB) in astrocytes. U0126, a pharmacological inhibitor of MEK, blocked the phosphorylation of the downstream elements ERK, RSK, and CREB, inhibited chemokine synthesis, and reduced transcription from a KC promoter construct. Dominant negative mutants of RSK or CREB blocked the transcription driven by the KC promoter. Finally, RANTES treatment induces nuclear translocation of phosphorylated RSK in astrocytes. This novel role for RSK in signaling chemokine responses and synthesis in astrocytes may contribute to the amplification mechanisms responsible for prolonging inflammatory responses in the central nervous system.
Zhang
Ye
Y
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Zhai
Qiwei
Q
Luo
Yi
Y
Dorf
Martin E
ME
D000818:Animals; D001253:Astrocytes / Q000201:enzymology / Q000378:metabolism*; D018946:Chemokine CCL5 / Q000502:physiology*; D018925:Chemokines / Q000235:genetics*; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D020935:MAP Kinase Signaling System; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D021381:Protein Transport; D011994:Recombinant Proteins / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D018946:Chemokine CCL5; D018925:Chemokines; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019893:Ribosomal Protein S6 Kinases