Interleukin-6 has potential as a therapeutic drug in treating metabolic disorders such as obesity, type 2 diabetes and atherosclerosis

For the most of the past century, researchers have searched for a muscle-contraction-induced factor, which mediates some of the exercise effects in other tissues and organs such as the liver and adipose tissue. In their quest for this magic trigger, or class of effectors, it’s been referred to as the “work stimulus,” “work factor” or the “exercise factor.”

Bente Karlund Pedersen, professor of internal medicine at Rigshospitalet and leader of the Muscle Center at the University of Copenhagen, Denmark, and her team are part of that search. They found a cytokine, Interleukin-6, which is produced by contracting muscles and released into the blood, and demonstrated that IL-6 has many biologic roles, including:

• Activation/inhibition of metabolic genes
• Induction of lipolysis, or the breakdown of fat
• Inhibition of insulin resistance, and
• Suppression of tumor necrosis factor (TNF) production.

In fact, Pedersen says the wide impact of muscle-derived IL-6 not only fulfills all the criteria for this “exercise factor” but that such classes of cytokines should be reclassified as “myokines.” She points out that because of its diverse effects, IL-6 has potential as a therapeutic drug in treating such metabolic disorders as obesity, type 2 diabetes and atherosclerosis.

Over the years, “increased levels of IL-6 after exercise is remarkably consistent,” Pedersen and a collaborator, Mark A. Febbraio of the Dept. of Physiology at the University of Melbourne, Australia, noted in an article in the FASEB Journal. However, the actual appearance of IL-6 into circulation depends on several factors including exercise intensity, duration and mode. For instance, vigorous rowing doubles the amount of IL-6 in plasma relatively quickly, while in endurance activity IL-6 doesn’t appear until later. Activation of the IL-6 gene seems to be enhanced when muscle glycogen content is low, while carbohydrate supplementation during exercise has been shown to inhibit the release of IL-6 from contracting muscle.

What does seem consistent is that IL-6 originates from the contracting limb and that skeletal muscle cells themselves are the likely source of production. The skeletal muscles seem to produce IL-6 in order to maintain metabolic homeostasis during periods of altered metabolic demand such as muscular exercise or insulin stimulation.

Such a powerful effector has also attracted some negative reaction, but Pedersen notes that IL-6 overall seems to have a “positive metabolic role in health and in the treatment of disease.” For instance high levels of IL-6 have been found in patients with “metabolic syndrome,” which may be explained by the fact that IL-6 is produced in adipose tissue. Similarly, increased levels of TNF-alpha and IL-6 have been observed in obese individuals, smokers and patients with non-insulin-dependent diabetes mellitus but there’s no evidence that either is actually the source of these problems.

Indeed, it’s possible, for instance, that IL-6 expression may be up-regulated in insulin resistant skeletal muscle in an attempt to overcome the impaired glucose uptake. And in other contexts, the current thinking is that IL-6 has primarily anti-inflammatory effects. It is this combination of effects that has prompted such widespread study.