Elevated GM-CSF levels in tumor bearing mice upregulate IL-6 production byB cells via a mechanism independent of TNF-alpha

During mammary tumorigenesis a profound dysregulation of cytokine productio n by various lymphoreticular cells has been documented. B lymphocytes from tumor bearers have an increased production of tumor necrosis factor a (TNF- alpha). We now report that these lymphocytes have elevated levels of interl eukin 6 (IL-6) at the transcriptional and translational levels, that are re flected systemically. The mammary tumor used in our study constitutively pr oduces several factors including granulocyte-macrophage colony stimulating factor (GM-CSF), prostaglandin E-2 (PGE(2)) and phosphatidyl serine (PS), w hich directly or indirectly can affect the cells of the immune system. In v itro addition of GM-CSF resulted in a dramatic increase in IL-6 levels from B cells from normal mice. This effect does not appear to be due to elevate d levels of TNF-alpha, known to upregulate IL-6 Rather, GM-CSF activates IL -6 production independently of TNF-alpha as demonstrated by neutralization studies using anti-TNF-alpha antibodies. Furthermore, the effect exerted by GM-CSF on IL-6 production by B lymphocytes appears to be direct since pret reatment of cultures with anti-GM-CSF completely abrogated the elevated pro duction of IL-6. The elevated levels of IL-6 and TNF-alpha in tumor bearers may contribute to the cachectic state observed in tumor bearing mice.