RETINOID ANTAGONISM OF NF-IL6 - INSIGHT INTO THE MECHANISM OF ANTIPROLIFERATIVE EFFECTS OF RETINOIDS IN KAPOSIS-SARCOMA

All-trans-retinoic acid (RA) is active in the treatment of Kaposi's sa rcoma (KS), and retinoids inhibit KS cell growth in vitro. To understa nd the mechanism of retinoid action in KS, we studied the expression o f autocrine growth factors of KS cells after RA treatment. We demonstr ate that RA and its synthetic analogs inhibit the proliferation of KS cells by inhibiting the mRNA and protein levels of interleukin-6 (IL-6 ), an autocrine growth factor for KS cells. We further demonstrate tha t nuclear retinoid receptors (RA receptors [RARs] and retinoid X recep tors [RXRs]) inhibit IL-6 promoter action by antagonizing the enhancer action of NF-IM, a basic domain leucine zipper transcription factor b elonging to the family of CAAT enhancer binding proteins. Furthermore, RARs and RXRs do not bind in vitro to an NF-IL6 binding site. However , the secondary folded structure of the DNA binding domain of RAR and RXR is obligatory for inhibiting NF-IL6 activity. Thus, NF-IL6 is a po tential therapeutic target for the treatment of KS. Finally, using rec eptor-selective synthetic retinoids, we demonstrate that NF-IL6 antago nism and transactivation are separable functions of RAR alpha, thus in dicating that synthetic retinoids with properties of NF-IL6 antagonism but lacking transactivation capabilities can be synthesized. Such ret inoids might increase therapeutic potential in KS.