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.
Charyulu
V I
VI
Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, FL 33136, USA.
Lopez
D M
DM
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation
D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor