INTERLEUKIN-6-INDUCED SERINE PHOSPHORYLATION OF TRANSCRIPTION FACTOR APRF - EVIDENCE FOR A ROLE IN INTERLEUKIN-6 TARGET GENE INDUCTION

The cytokine interleukin-6 (IL-6) rapidly activates a latent cytoplasm ic transcription factor, acute-phase response factor (APRF), by tyrosi ne phosphorylation. Activation and DNA binding of APRF are inhibited b y inhibitors of protein tyrosine kinases but not serine/threonine kina ses. However, immediate-early gene induction by IL-6 and, as we show h ere, stimulaton of the promoters of the genes for alpha(2)-macroglobul in, Jun-B, and intercellular adhesion molecule-1 (ICAM-1) are blocked by the serine/threonine kinase inhibitor H7. We now show that IL-6 tri ggers a delayed phosphorylation of APRF at serine resudues which can b e reversed in vitro by protein phosphatase 2A and is also inhibited by H7. Therefore, APRF serine phosphorylation is likely to represent a c rucial event in IL-6 signal transduction leading to target gene induct ion.