Inflammation and neural signaling

Abstract

Purpose of review Cancer patients undergoing treatment with cytotoxic chemotherapeutic agents (CCAs) often experience a cluster of treatment-related symptoms, which include fatigue, loss of appetite, disturbed sleep, depressed mood, cognitive difficulties, and changes in body composition. This symptom cluster collectively referred to herein as cancer treatment-related symptoms (CTRSs) decrease quality of life, and physical and social functioning. The preclinical and clinical studies described in this review represent important progress in understanding potential underlying mechanisms of CTRS. Recent findings Recent studies support a role for CCA-induced interleukin-1β (IL-1β) signaling in the cause of CTRS. CCAs may share a common ability to activate intracellular stress response pathways to trigger the synthesis, processing, and release of IL-1β from immune cells. Fatigue, sleep disturbance, and cognitive difficulties in cancer patients exposed to CCAs correlate with plasma levels of IL-6, IL-1 receptor antagonist, and soluble tumor necrosis factor receptor-I/II, surrogate markers of IL-1β-mediated central nervous system (CNS) inflammation. Additional preclinical work suggests IL-1β-mediated CNS inflammation may cause CTRS by altering hypothalamic and hippocampal functioning. Summary Although additional research is necessary to further establish the link between CCA exposure, IL-1β-mediated inflammatory processes and CTRS, these data provide hints for future studies and therapeutic approaches in ameliorating these symptoms in cancer patients.

A review of the neuro- and systemic inflammatory responses in post concussion symptoms: Introduction of the “post-inflammatory brain syndrome” PIBS

“…Speculation exists about a role for inflammation in the cancer treatment-related syndrome cluster due to the stimulation of Il-1b production in macrophages in response to some chemotherapeutic agents. While increased levels of peripheral Il-1b are not seen in humans after chemotherapy, increased levels of Il-6 and Il-1ra are seen in the treatment-related symptom cluster and are correlated with fatigue and sleep changes, and these markers are proposed as markers of central Il-1b activity (Wood and Weymann, 2013). In women with ovarian cancer, both before and after surgery, sleep disturbances are associated with higher levels of Il-6 (Clevenger et al, 2012).…”

Tumor growth increases neuroinflammation, fatigue and depressive-like behavior prior to alterations in muscle function

“…Mounting evidence indicates that CRF and depressed mood are associated with elevated serum levels of pro-inflammatory mediators, including C-reactive protein (Pertl et al, 2013) and cytokines such as tumor necrosis factor-alpha (TNFα), interleukin (IL)-1β and IL-6 (Saligan and Kim, 2012; Wood and Weymann, 2013). These cytokines are likely produced by the tumor and host tissues in response to tumor growth or anti-tumor treatments (Wang et al, 2012).…”

“…The central nervous system (CNS) interprets inflammatory responses that originate in the periphery. Microglia, innate immune cells of the CNS, contribute to the propagation of inflammatory cytokines and secondary messengers throughout the CNS (Wood and Weymann, 2013). Increases in brain IL-1β are linked to both muscle atrophy (Braun et al, 2011) and depressed mood (Haroon et al, 2012).…”

Fluoxetine prevents the development of depressive-like behavior in a mouse model of cancer related fatigue

“…Mounting evidence from both clinical and preclinical studies indicates that elevations in pro-inflammatory cytokines may function as a common mechanism for the frequent association of fatigue and depression in patients with CRF. For instance, elevated serum levels of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNFα), interleukin (IL)-1β and IL-6, are associated with fatigue in cancer patients [12, 13]. Increases in systemic inflammation are relayed to the brain where inflammation is propagated by innate immune cells [14].…”