The Immunomodulator AS-101 Inhibits IL-10 Release and Augments TNFα and IL-1α Release by Mouse and Human Mononuclear Phagocytes

AS-101 is a tellurium-based compound with known immunomodulating properties. The ability of AS-101 to potentiate the effects of chemotherapeutic drugs and augment cytokine productionin vivohas led to clinical trials on AS-101 which are currently being carried out in cancer patients. In the present study we show that AS-101 selectively augments the release of TNFα and IL-1α and inhibits the release of IL-10 by lipopolysaccharide (LPS)-stimulated mouse peritoneal macrophages and human monocytes. It does not significantly affect the release of IL-6 or leukemia inhibitory factor (LIF). By itself AS-101 does not induce the release of any of these cytokines. Analysis of IL-10 and TNFα RNA levels using semiquantitative PCR reveals that AS-101 blocks the transcription of IL-10 mRNA, but does not significantly affect TNFα mRNA. Although both AS-101 and interferon (IFN)-γ inhibit IL-10, AS-101, unlike IFN-γ, does not prime macrophages for LPS-induced nitric oxide release and does not appear to significantly affect monocyte HLA-DR expression. Our data suggest that AS-101 is a partial IFN-γ agonist and may explain the shift toward the release of Th-1 type cytokines observed in AS-101-treated patients.