ENHANCEMENT OF GP130-MEDIATED TYROSINE PHOSPHORYLATION OF STAT3 AND ITS DNA-BINDING ACTIVITY IN DEXAMETHASONE-TREATED AIDS-ASSOCIATED KAPOSIS-SARCOMA CELLS - SELECTIVE SYNERGY BETWEEN DEXAMETHASONE AND GP130-RELATED GROWTH-FACTORS IN KAPOSIS-SARCOMA CELL-PROLIFERATION

The soluble IL-6R (sIL-6R alpha)/IL-6 complex and oncostatin M (OM), w hich exert biologic activities through the signal-transducing protein gp130, are potent growth factors for AIDS-associated Kaposi's sarcoma (KS) cells, Clinical observations indicate that glucocorticoid therapy is a possible risk factor in KS; however, little is known of specific interactions in KS cells between glucocorticoid and gp130-related gro wth factors, We obtained evidence that dexamethasone (Dex), in a syner gistic manner, enhances gp130-mediated growth of KS cells, Anti-gp130 Abs or the glucocorticoid antagonist RU-486 abolished this synergistic effect, In addition, Dex had additive but not synergistic effects on stimulation of KS cell growth with IL-1 beta or TNF-alpha, the signals of which are not mediated through gp130, Immunoblot analysis revealed sIL-6R alpha/IL-6- or OM-induced tyrosine phosphorylation of a simila r set of proteins in KS cells, and which was augmented significantly i n Dex-treated KS cells, Stimulation of KS cells with sIL-6R alpha/IL-6 or OM induced rapid tyrosine phosphorylation of the transcription fac tor STAT3, and Dex significantly enhanced the accumulation of tyrosine -phosphorylated STAT3, Electrophoretic mobility shift assays showed sI L-6R alpha/IL-6- or OM-induced DNA-binding activity of STAT3 in KS cel ls, and Dex further increased this activity, Thus, Dex appears to part icipate in the gp130-STAT3 signaling and transcriptional events by enh ancing STAT3 activation, thereby leading to selective synergistic stim ulation of KS cell growth with Dex and the gp130-related growth factor s.