Interleukin (IL)-6: Comparison
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Interleukin (IL)-6 is a signaling molecule involved in inflammatory processes, initiating fever and mediating the acute phase response. It is a pleiotropic cytokine secreted by a range of cells, such as T cells, B cells, macrophages, osteoblasts, smooth muscle cells and several tumor cells. It is also released by cells in the brain, such as neurons, microglia and astrocytes.

  • Interleukin (IL)-6

1. Introduction

Interleukin (IL)-6 is a signaling molecule involved in inflammatory processes, initiating fever and mediating the acute phase response. It is a pleiotropic cytokine secreted by a range of cells, such as T cells, B cells, macrophages, osteoblasts, smooth muscle cells and several tumor cells. It is also released by cells in the brain, such as neurons, microglia and astrocytes. IL-6 has been implicated in inflammatory and auto-immune processes related to a wide range of diseases such as diabetes [1], atherosclerosis [2], depression [3], rheumatoid arthritis [4] and Castleman’s disease [5], as well as several cancers [6][7][8] and cancer cachexia [9][10]. Given IL-6′s implication in disease states, several agents inhibiting the IL-6 signaling pathway have been developed as pharmacological treatments for some of these diseases, e.g., rheumatoid arthritis, Castleman’s disease and prostate cancer. Inhibiting the action of IL-6 can be achieved either by targeting the soluble IL-6 molecule or by blocking the cell surface receptor (IL-6R) on which IL-6 attaches. The latter are known as IL-6 receptor antagonists, and the first FDA-approved medication targeting IL-6 signaling, tocilizumab, belongs to this class. Another monoclonal antibody against IL-6R is sarilumab, which has been recently approved by the FDA for the treatment of rheumatoid arthritis. Conversely, siltuximab directly targets the IL-6 soluble molecule and there are several other agents (olokizumab, elsilimomab, sirukumab) in this class that are currently being tested and are at various phases of clinical trials.

Aside from its involvement in disease states, IL-6 has been shown to play a role in the control of body weight and body fat. For example, in animal studies, overexpression of IL-6 has been reported to reduce fat accumulation and weight gain [11][12][13], whereas IL-6-deficient mice develop mature-onset obesity [14][15]. Previous research points to a complex relationship between IL-6 and body weight and fat. It is generally accepted that high levels of inflammatory mediators such as IL-6 and TNF-a are cachectogenic [9][16][17] and perhaps anorexigenic [18][19], i.e., associated with weight loss and decreased food intake. However, in the context of obesity, low-grade elevation of inflammatory markers is observed, as both aforementioned cytokines are produced by adipose tissue [20][21][22]. Therefore, it is unclear how IL-6 signaling inhibitors may influence weight and/or fat mass.

Generally, administration of IL-6 pathway inhibitors has been associated with an increase in body weight and body mass index (BMI) [23][24], implying that IL-6 signaling inhibition might lead to weight gain as a side-effect. Given the known health risks associated with obesity, it would be of value for clinicians to have reliable information about whether IL-6 signaling inhibitors systematically induce weight gain, in order to aid their decision-making. Additionally, if IL-6 pathway inhibitors induce weight gain, blocking IL-6 signaling could become a novel adjunct strategy for the treatment of disorders with severely low body weight such as cancer cachexia and anorexia nervosa.

2. Possible Mechanisms of IL-6-Induced Weight Loss

IL-6 is a functionally pleiotropic cytokine implicated in inflammation and infection responses as well as the regulation of metabolic and neural processes. It has many cell-type specific effects and although primarily regarded as a pro-inflammatory cytokine, IL-6 also has many regenerative or anti-inflammatory properties. Given its wide variety of actions IL-6 has been implicated in many aspects of (patho)physiology, including weight and/or fat mass changes. Research thus far points towards a dual role of IL-6 in the central nervous system (CNS) and the periphery.

2.1. Effects on Appetite

With regards to IL-6′s effects on the CNS, there is some evidence indicating that IL-6 might lead to weight loss through a reduction in food intake and/or appetite suppression. For example, in animal studies, where IL-6 was administered intracerebroventricularly, it led to a suppression of food intake, whereas when IL-6 was administered at the same dose intraperitoneally there was no effect on food intake [25][26]. Mishra et al. [26] have postulated that IL-6 exerts its anorexigenic effects through interaction with leptin. Another possible mechanism by which IL-6 could be exerting food intake/appetite control is through its effects on hypothalamic neuropeptides such as neuropeptide Y, agouti-related peptide, melanin-corticotrophin-releasing hormone and pro-opiomelanocortin [13]. With regards to studies in humans, the effect of IL-6 on appetite has been reported by some authors. For example, Hunschede et al. [27] found elevated levels of IL-6 following high intensity exercise in normal weight and obese boys, which was inversely correlated with appetite and fullness. Furthermore, Emille et al. [28] suggested that the observed clinical improvement seen in seven of the eight patients completing treatment with an IL-6 signaling pathway inhibitor for their lymphoma, was due to increased appetite. In a second study by Hunschede et al. [29], it was found that IL-6 correlated with active ghrelin and cortisol, and hence the authors hypothesized that the effects of IL-6 on appetite are potentially mediated by ghrelin and cortisol signaling. In contrast, Li et al. [11] and Hidalgo et al. [12] who centrally expressed murine IL-6 in the hypothalamus of rats found that although weight gain and visceral adiposity was suppressed, food intake was not affected. Thus, research to this date has not consistently confirmed the potential anorexigenic role of IL-6 in the CNS.

2.2. Effects on Metabolism

Given the conflicting results of IL-6 effects on food intake and appetite control, it is plausible that other mechanisms are at least partially at play. Alterations in fat mass and body weight without changes in food intake suggest that IL-6 may affect energy metabolism. One of the hallmarks of obesity-related metabolic disorders is chronic, low-grade inflammation. This systemic overabundance of proinflammatory cytokines in adipose tissue, including IL-6, activates STAT3 and subsequently AMPK [30][31] leading to alterations in insulin signaling and eventually Type 2 diabetes [32][33].

On the other hand, there is increasing evidence suggesting a beneficial role for IL-6 in the prevention of obesity and insulin resistance. For example, Carey at al. found that IL-6 increases glucose disposal in healthy humans [30][34]. Additionally, IL-6 deficient mice develop mature-onset obesity, partially attributed to reduced energy expenditure [15], and conversely, overexpression of IL-6 leads to increased thermogenesis [26] energy expenditure [11].

The longstanding assertion that IL-6 leads to insulin resistance has been challenged by the discovery of IL-6′s actions in muscle. Pedersen et al. found that IL-6 acts as a myokine, meaning it is produced and released by muscle cells in response to muscular contractions [35][36], and physical exercise is known to increase insulin sensitivity [37][38]. While there are conflicting findings, it is clear that IL-6 is implicated in the regulation of energy homeostasis, and it is thus possible that IL-6 signaling inhibitors may contribute to changes in weight and fat mass.

2.3. Clinical Implications

The findings suggest that administration of IL-6 signaling pathway inhibitors could lead to weight gain. In instances where obesity is considered a risk factor and an exacerbator of disease, the additional weight gain due to anti-IL-6 administration may be an undesirable effect, and given the well-documented detrimental effects associated with obesity (e.g., cardiovascular disease, metabolic syndrome, mental health problems [39][40][41]), prescribers should take this into consideration when administering IL-6 pathway inhibitors. For such cases, clinical monitoring of patients’ weight with additional weight-regulating measures, such as diet counselling and physical exercise, may be necessary. It is important to mention here that weight gain may not be specific to IL-6 signaling inhibition as other cytokine inhibitors have also been shown to increase weight and BMI [42].

Pharmacological modulation of IL-6 signaling through IL-6 blockade may be a potential route of action for diseases or disorders with a significant weight loss component, such as cancer cachexia and anorexia nervosa. For example, we previously reported elevated levels of IL-6 in anorexia nervosa patients [19], suggesting modulating cytokines such as IL-6 could be a possible treatment option for patients with anorexia nervosa [43][44]. However, IL-6 blockade is associated with other serious side-effects and the clinical use of such medication for the purpose of weight gain should be carefully considered, as the expected weight gain may not justify the burden of additional drug effects.

3. Conclusions

The results show a small but significant increase in weight and BMI following treatment with an IL-6 pathway inhibitor. This is line with a large body of research performed on animals, as well as in clinical populations, that implicates IL-6 in the control of weight, appetite, and energy metabolism. As weight gain appears to be a side-effect of inhibitors of IL-6 signaling, they may be a potential pharmacological adjunct for the treatment of cancer cachexia and anorexia nervosa.

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