Abstract B16 melanoma F10 (B16-F10) cells with high glutathione (GSH) content show very high metastatic activity in vivo. An intertissue flow of GSH, where the liver is the main reservoir, increases GSH content in metastatic cells and promote their growth. We studied possible tumor-derived molecular signals that could activate GSH release from hepatocytes. GSH efflux increases in hepatocytes isolated from mice bearing liver or lung metastases, thus suggesting a systemic mechanism. Fractionation of serum-free conditioned medium from cultured B16-F10 cells and monoclonal antibody-induced neutralization techniques facilitated identification of interleukin (IL)-6 as a tumor-derived molecule promoting GSH efflux in hepatocytes. IL-6 activates GSH release through a methionine-sensitive/organic anion transporter polypeptide 1- and multidrug resistance protein 1-independent channel located on the sinusoidal site of hepatocytes. Specific siRNAs were used to knock down key factors in the main signaling pathways activated by IL-6, which revealed a STAT3-dependent mechanism. Our results show that IL-6 (mainly of tumor origin) facilitates GSH release from hepatocytes and its interorgan transport to metastatic growing foci. Metastatic tumor activated the hypothalamic-pituitary-adrenal axis, thus increasing expression of hypothalamic corticotropin releasing factor and plasma levels of adrenocorticotropin hormone, corticosterone, and cathecolamines. Corticosterone and norepinephrine increased IL-6 expression and synthesis in metastatic cells, thus promoting the interorgan GSH/IL-6 cycling activity. Our results suggest possible mechanisms of cross-talk between metastases and the central nervous system of the host. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2427. doi:1538-7445.AM2012-2427