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 Bl and gene knockout mice to evaluate the role of host-produced cytokines [interleukin (IL)-6, IL-12, IFNgamma, tumor necrosis factor (TNF) receptor 1, and TNF receptor 2] to explain local tumor growth, anorexia, and carcass weight loss in a well-defined model with experimental cachexia. Indomethacin was provided in the drinking water to explore interactions between host and tumor-derived prostaglandins and proinflammatory cytokines for tumor growth. Wild-type tumor-bearing mice developed cachexia because of rapid tumor growth, which were both attenuated in IL-6 gene knockouts. Similar findings were observed after provision of anti-IL-6 to wild-type tumor-bearing mice. Alterations in food intake 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 1 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 IL-6. Systemic indomethacin provision decreased plasma prostaglandin E2 in five of six groups of gene knockout tumor-bearing mice, which was associated with improved carcass weight in these groups. Indomethacin seemed to improve food intake to a similar extent in both wild-type and gene knockouts, which agree with the speculation that eicosanoids are more important to explain anorexia than host cytokines. Our results demonstrate that host- and tumor-derived cytokines and prostaglandins interact with tumor growth and promote cachexia in a more complex fashion than usually presented based on previous 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.
Cahlin
C
C
Department of Surgery, Sahlgrenska University Hospital, Göteborg University, Sweden.
Körner
A
A
Axelsson
H
H
Wang
W
W
Lundholm
K
K
Svanberg
E
E
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000906:Antibodies / Q000494:pharmacology; D001835:Body Weight / Q000502:physiology; D002100:Cachexia / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000502:physiology; D016207:Cytokines / Q000235:genetics / Q000502:physiology*; D015232:Dinoprostone / Q000097:blood; D004435:Eating / Q000502:physiology; D015777:Eicosanoids / Q000097:blood / Q000502:physiology*; D007213:Indomethacin / Q000494:pharmacology; D007371:Interferon-gamma / Q000235:genetics / Q000502:physiology; D018664:Interleukin-12 / Q000235:genetics / Q000502:physiology; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D012513:Sarcoma, Experimental / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000906:Antibodies; D016207:Cytokines; D015777:Eicosanoids; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma; D015232:Dinoprostone; D007213:Indomethacin