Role of interleukin-6 in cachexia

Abstract

Purpose of review Interleukin-6 (IL-6) has emerged as a cytokine involved in cachexia progression with some cancers. This review will present recent breakthroughs in animal models and humans related to targeting IL-6 as a cancer cachexia therapy. Recent Findings IL-6 can target adipose, skeletal muscle, gut, and liver tissue, which can all affect cachectic patient recovery. IL-6 trans-signaling through the soluble IL-6r has the potential to amplify IL-6 signaling in the cachectic patient. In skeletal muscle chronic IL-6 exposure induces proteasome and autophagy protein degradation pathways that lead to wasting. IL-6 is also indirectly associated with AMPK and NF-κB activation. Several mouse cancer models have clearly demonstrated that blocking IL-6 and associated signaling can attenuate cachexia progression. Additionally, pharmaceuticals targeting IL-6 and associated signaling can relieve some cachectic symptoms in cancer patients. Research with cachectic mice has demonstrated that exercise and nutraceutical administration can interact with chronic IL-6 signaling during cachexia progression. Summary IL-6 remains a promising therapeutic strategy for attenuating cachexia progression with many types of cancer. However, improvement of this treatment will require a better understanding of the indirect and direct effects of IL-6 as well as its tissue specific actions in the cancer patient.

Xilonix, a novel true human antibody targeting the inflammatory cytokine interleukin-1 alpha, in non-small cell lung cancer

“…IL-6 has also been identified as a potential target in the treatment for the symptoms of cancer associated cachexia(35). The concept of this inflammatory cytokine contributing to the development of drug resistance however, is relatively new and certainly intriguing.…”

Smad7 gene delivery prevents muscle wasting associated with cancer cachexia in mice

“…These results are not surprising, because the muscle-targeted approach of rAAV6:Smad7 would not be expected to directly influence adipose physiology. Ameliorating lipolysis in cachexia may be more effectively achieved by jointly targeting other cachexiaassociated cytokines, such as IL-6 and TWEAK (25,39), although conserving lean mass and muscle function is arguably the primary goal for interventions aimed at prolonging survival (2,6,40). Of particular note, the systemic administration of rAAV6:Smad7 also prevented cardiac atrophy in tumor-bearing mice, because rAAV6 vectors administered via the circulation can transduce cardiac muscle.…”

“…However, because tumor-and host-derived interleukin-6 (IL-6) is also implicated in the etiology of cachexia (3,25), we examined whether the protective effects of Smad7 were associated with altered IL-6 signaling. Administration of rAAV6:Smad7 did not alter circulating levels of IL-6 (Fig.…”

Molecular Pathways: Cachexia Signaling—A Targeted Approach to Cancer Treatment

“…Multiple cytokines, including TNF-α, IL-1 and IL-6, have been implicated in facilitating a cachectic state (12), and their expression or upregulation is prompted by both tumor and host derived factors. High serum levels of these cytokines are present in many cancer patients with cachexia.…”