Mechanisms of experimental cancer cachexia. Interaction between mononuclear phagocytes and colon-26 carcinoma and its relevance to IL-6-mediated cancer cachexia.
In a recent report we showed that IL-6 is an important mediator of experimental cancer cachexia in the colon-26 (C-26) tumor system. In culture, on a per cell basis, C-26.IVX cell line (which develops tumors and induces severe cachexia of syngeneic hosts) produces up to 60-fold less IL-6 than single cell suspensions prepared from freshly excised tumors. In this study, the mechanism behind this observation was investigated. Analysis of the cellular composition of progressing C-26 tumors indicated they contained up to 6% of macrophages. T cells, B cells, and granulocytes were not detected in the tumors. Because C-26.IVX line grown in vitro contained no macrophages, the possibility that macrophage products may augment IL-6 synthesis by the tumor cells was tested. Indeed, IL-1 beta in a dose-dependent manner and at picogram amounts could potentiate IL-6 production by the C-26 cell line. The presence of high affinity receptors for IL-1 on the C-26.IVX cell line was established. These cells expressed approximately 1500 IL-1 sites per cell with a dissociation constant of approximately 20 pM. Next, we attempted to mimic the situation in vivo by coculture of C-26.IVX cells with syngeneic peritoneal macrophages and found that this condition gives rise to an augmented IL-6 production similar to that observed with in vivo derived tumor cells or rIL-1 beta-treated C-26.IVX cells. Furthermore, anti-IL-1 type I receptor antibody completely blocked C-26.IVX IL-6 production induced by either rIL-1 beta or by peritoneal macrophages. Taken together, these data suggest a pathway of IL-6 production by C-26 tumors that involves a cellular interaction between IL-1R-expressing tumor cells and host-derived macrophages. The results also suggest that this interaction significantly contributes to cachectic events endured by the tumor-bearing host.
Strassmann
G
G
Department of Immunology, Otsuka America Pharmaceutical, Inc., Rockville, MD 20850.
Jacob
C O
CO
Evans
R
R
Beall
D
D
Fong
M
M
D000818:Animals; D002100:Cachexia / Q000503:physiopathology*; D002277:Carcinoma / Q000503:physiopathology*; D003110:Colonic Neoplasms / Q000503:physiopathology*; D015870:Gene Expression; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D011971:Receptors, Immunologic / Q000378:metabolism; D017472:Receptors, Interleukin-1; D014407:Tumor Cells, Cultured
D007375:Interleukin-1; D015850:Interleukin-6; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1