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

During mammary tumorigenesis a profound dysregulation of cytokine production by various lymphoreticular cells has been documented. B lymphocytes from tumor bearers have an increased production of tumor necrosis factor alpha (TNF-alpha). We now report that these lymphocytes have elevated levels of interleukin 6 (IL-6) at the transcriptional and translational levels, that are reflected systemically. The mammary tumor used in our study constitutively produces several factors including granulocyte-macrophage colony stimulating factor (GM-CSF), prostaglandin E2 (PGE2) and phosphatidyl serine (PS), which directly or indirectly can affect the cells of the immune system. in vitro 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 elevated 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 pretreatment of cultures with anti-GM-CSF completely abrogated the elevated production 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.