CROSSTALK BETWEEN THE INTERLEUKIN-6 (IL-6)-JAK-STAT AND THE GLUCOCORTICOID-NUCLEAR RECEPTOR PATHWAY - SYNERGISTIC ACTIVATION OF IL-6 RESPONSE ELEMENT BY IL-6 AND GLUCOCORTICOID

Cytokines and steroid hormones use different sets of signal transducti on pathways, which seem to be unrelated. Interleukin-6 (IL-6) uses JAK tyrosine kinase and STAT (signal transducer and activator of transcri ption) transcription factor. Glucocorticoid binds glucocorticoid recep tor (GR), which is a member of the steroid receptor superfamily. We ha ve studied the crosstalk between the IL-6-JAK-STAT and glucocorticoid- nuclear receptor pathways. IL-6 and glucocorticoid synergistically act ivated the IL-6 response element on the rat alpha(2)-macroglobulin pro moter (APRE)-driven luciferase gene. The exogenous expression of GR en hanced the synergism. The exogenous expression of dominant negative ST ATS completely abolished the IL-6 plus glucocorticoid-induced activati on of the APRE-luciferase gene. Tyrosine phosphorylation of STAT3 stim ulated by IL-6 alone was not different from that by IL-6 plus glucocor ticoid. The protein level of STAT3 was also not increased by glucocort icoid stimulation. The time course of STAT3 tyrosine phosphorylation b y IL-6 plus glucocorticoid was not different from that by IL-6 alone. The synergism was studied on the two other IL-6 response elements, the junB promoter (JRE-IL-6) and the interferon regulatory factor-1 (IRF- 1) promoter (IRF-GAS) which could be activated by STAT3. The synergist ic activation by glucocorticoid on the IL-6-activated JRE-IL-6 and the IRF-GAS-driven luciferase gene was not detected. Glucocorticoid did n ot change the mobility of IL-6-induced APRE-binding proteins in a gel shift assay. These results suggest that the synergism was through the GR and STAT3, and the coactivation pathway which was specific for APRE was the target of glucocorticoid.