ANTIOXIDANT-SENSITIVE REGULATION OF INFLAMMATORY-RESPONSE GENES IN KAPOSIS-SARCOMA CELLS

Kaposi's sarcoma (KS) is a multifocal vascular lesion characterized by abnormal proliferation of endothelial-like KS cells linked to a prono unced leukocyte infiltration. KS lesions contain novel herpes-like DNA sequences, KSHV, hypothesized to originate from the viral pathogen fo r KS. Using cultured KS cells that retain the KSHV sequences, diverse signals, including tumor necrosis factor alpha, interleukin (IL) 1 bet a, polyinosinic acid/polycytidylic acid, and lipopolysaccharide, induc ed the expression of the cytokine IL-6 and cellular adhesion molecules involved in leukocyte recruitment, including vascular adhesion molecu le 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1). The thio l-antioxidant pyrrolidine dithiocarbamate (PDTC) selectively inhibited >90% of the activation of nuclear factor KB-like DNA binding activity in KS cells. PDTC also reduced by >85% induced levels of VCAM-1 and I L-6 at the mRNA, protein, and functional levels in KS cells. In contra st, PDTC did not inhibit the induced expression of either ICAM-1 or E- selectin. These studies show that PDTC differentially modulates the ex pression of inflammatory response genes in KS cells that contain KSHV, suggesting that reduction-oxidation-sensitive events are involved in the regulation of these genes. These studies also suggest that thiol-a ntioxidants such as PDTC may play a potentially therapeutic role in th e treatment of KS by preventing induction of specific inflammatory res ponse genes that may be involved in the pathogenesis of KS.