Tumor-Associated Fatigue in Cancer Patients Develops Independently of IL1 Signaling

Abstract

<p class="first" id="P1">Fatigue is the most common symptom of cancer at diagnosis, yet causes and effective treatments remain elusive. As tumors can be highly inflammatory, it is generally accepted that inflammation mediates cancer-related fatigue. However, evidence to support this assertion is mostly correlational. In this study, we directly tested the hypothesis that fatigue results from propagation of tumor-induced inflammation to the brain and activation of the central pro-inflammatory cytokine, interleukin-1 (IL-1). The heterotopic syngeneic murine head and neck cancer model (mEER) caused systemic inflammation and increased expression of <i>Il1b</i> in the brain while inducing fatigue-like behaviors characterized by decreased voluntary wheel running and exploratory activity. Expression of <i>Il1b</i> in the brain was not associated with any alterations in motivation, measured by responding in a progressive ratio schedule of food reinforcement, depressive-like behaviors, or energy balance. Decreased wheel running occurred prior to <i>Il1b</i> detection in the brain, when systemic inflammation was minimal. Further, mice null for two components of IL-1β signaling, the type 1 interleukin-1 receptor or the receptor adapter protein MyD88, were not protected from tumor-induced decreases in wheel running, despite attenuated cytokine action and expression. Behavioral and inflammatory analysis of 4 additional syngeneic tumor models revealed that tumors can induce fatigue regardless of their systemic or central nervous system inflammatory potential. Together our results show that brain IL-1 signaling is not necessary for tumor-related fatigue, dissociating this type of cancer sequela from systemic cytokine expression. </p>