Role of interleukin-6 in cachexia: therapeutic implications

Abstract

Purpose of review: Interleukin-6 (IL-6) has emerged as a cytokine involved in cachexia progression with some cancers. This review will present the 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 the skeletal muscle, chronic IL-6 exposure induces proteasome and autophagy protein degradation pathways that lead to wasting. IL-6 is also indirectly associated with AMP-activated kinase (AMPK) and nuclear factor kappa B (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.

Figure 1. IL-6 signaling and its downstream targets in skeletal muscle

The IL-6/IL-6R complex or IL6/sIL-6R complex can signal through the membrane bound gp130 receptor to activate both the STAT-3 and ERK cascade (Direct targets in gray). Activation of the IL – 6 signaling cascade leads to the activation of various proliferative, anti-inflammatory and anti – apoptotic, and inflammatory genes downstream. Indirect targets (In Black) of IL – 6 include AMPK and NF – kB which are upregulated with IL -6 induced cachexia in vivo, however these cannot be attenuated by IL – 6 inhibitors. Pre – clinical trials have tested antibodies against the IL – 6 receptor and various inhibitors for the JAK/STAT-3 signaling to study the effect of IL – 6 on cachexia progression. Based on these studies currently antibodies against IL -6 (ALD518 and siltuximab) and its receptor (Tocilizumab) are being tested for attenuation of cachexia in patients. The black arrows ending in a circle represent inhibitory pathways. The gray arrow ending in a “V” represent activation pathways

Figure 2. Representative figure demonstrating the systemic effect of IL - 6 dependent cachexia in vivo

IL - 6 source mainly from the tumor and immune cells like macrophages affects various organs like adipose, muscle liver and gut with contrasting effects. Adipose tissue undergoes rapid lipolysis under chronic IL-6 conditions [6, 13, 19]. Muscle demonstrates activation of inflammatory and degradation pathways with a suppression of protein synthesis signaling. The liver demonstrates hypertrophy, an upregulation of innate inflammatory pathways, with a possible suppression of adaptive responses and disruption in lipid signaling. The gut is affected by chronic IL - 6 exposure with increased gut permeability possible due to a disruption in tight junction proteins and anemia. Both increased gut permeability and liver dysfunction may contribute to endotoxemia seen in the later stages of cachexia. Abbreviations: TJ = Tight junctions, APR = Acute Phase Response, VLDL = Very low density lipoproteins. Images in the figure were downloaded and adapted from an online image library: dreamstime royaltyfree stock photos. http://www.dreamstime.com/photos-images.html.