Experimental cancer cachexia: The role of host-derived cytokines interleukin (IL)-6, IL-12, interferon-gamma, and tumor necrosis factor alpha evaluated in gene knockout, tumor-bearing mice on C57 Bl background and eicosanoid-dependent cachexia

MCG 101 tumors were implanted sc. on wild-type C57 B1 and gene knockout mic e to evaluate the role of host-produced cytokines [interleukin (IL)-6, IL-1 2, IFN gamma, tumor necrosis factor (TNF) receptor 1, and TNF receptor 2] t o explain local tumor growth, anorexia, and carcass weight loss in a well-d efined model with experimental cachexia, Indomethacin was provided in the d rinking water to explore interactions between host and tumor-derived prosta glandins and proinflammatory cytokines fur tumor growth. Wild-type tumor-be aring mice developed cachexia because of rapid tumor growth, which were bot h attenuated in IL-6 gene knockouts. Similar findings were observed after p rovision of anti-IL-6 to wildtype tumor-bearing mice. Alterations in food i ntake were not directly related to systemic IL-6 but rather secondarily to IL-6-dependent tumor growth. The absence of host-derived IL-12, IFN-gamma, or the TNF receptor I or receptor 2 gene did not attenuate tumor growth or improve subsequent cachexia, Thus, carcass weight loss was not improved by the omission of host cytokine (TNF-alpha, IL-12, or IFN-gamma) except for I L-6, Systemic indomethacin provision decreased plasma prostaglandin E-2 in five of six groups of gene knockout tumor-bearing mice, which was associate d with improved carcass weight in these groups. Indomethacin seemed to impr ove food intake to a similar extent in both wild-type and gene knockouts, w hich agree with the speculation that eicosanoids are more important to expl ain anorexia than host cytokines. Our results demonstrate that host- and tu mor-derived cytokines and prostaglandins interact with tumor growth and pro mote cachexia in a more complex fashion than usually presented based on pre vious information in studies on either anti-cytokine experiments in vivo or on gene knockouts with respect to a "single cytokine model." Overall, host cytokines were quantitatively less important than tumor-derived cytokines to explain net tumor growth, which indirectly explains subsequent cachexia and anorexia.