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Cytokine and Cyclooxygenase-2 Protein in Brain Areas of Tumor-bearing Mice with Prostanoid-related Anorexia¹

Surgical Metabolic Research Laboratory, Lundberg Laboratory for Cancer Research, Department of Surgery, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden

Evidence suggests that cytokines in the central nervous system are mediators behind anorexia in tumor-bearing hosts. We have therefore evaluated, by immunohistochemical image analyses, time course changes of interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF) , IL-6 receptor (gp130), IL-1 receptor I, and cyclooxygenase (Cox)-2 protein in brain cortex, hippocampus and the ventromedial hypothalamic nucleus (VMH) in tumor-bearing mice with prostanoid-related anorexia. Pair-fed non-tumor-bearing mice were used as controls. Prostaglandin E₂ was provided systemically to freely fed, non-tumor-bearing mice to confirm a role for prostanoids in modulation of brain cytokines and food intake.

Time course changes of IL-1ß were significantly different between tumor-bearing mice and pair-fed controls in the hippocampus but not in the VMH. TNF- in the hippocampus and VMH did not show any significant difference between tumor-bearing mice and pair-fed controls, whereas TNF- showed a small increase over time in brain VMH. IL-6 content did not show any significant alterations among tumor-bearing and pair-fed mice but increased significantly over time in both the study and control group. Cox-2 in brain hippocampus and VMH showed a statistically significant rise in both tumor-bearing and pair-fed controls, with no difference between animal groups. Systemic provision of exogenous PGE₂ to non-tumor-bearing mice altered brain cytokines significantly in the hippocampus and VMH with associated changes in food intake. Our results demonstrate that some differences (IL-1ß) occurred in brain cytokines comparing tumor-bearing and pair-fed, non-tumor-bearing mice but within unexpected decreased levels in brain tissue from tumor-bearing mice. Surprisingly, many time course changes in brain cytokines were similarly altered in tumor-bearing and pair-fed mice. Our observations do not support that up-regulation of brain cytokines explains or promotes anorexia in cancer disease. Rather, cytokine and Cox-dependent alterations in brain tissue seemed to be secondary to a decline in food intake and related to subsequent stress hormone activities.

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