Interleukin-6 myokine signaling in skeletal muscle: a double-edged sword?
TL;DR: Paradoxically, deleterious actions for IL‐6 have also been proposed, such as promotion of atrophy and muscle wasting, and the current evidence for these apparently contradictory effects is reviewed.
Abstract: Interleukin (IL)-6 is a cytokine with pleiotropic functions in different tissues and organs. Skeletal muscle produces and releases significant levels of IL-6 after prolonged exercise and is therefore considered as a myokine. Muscle is also an important target of the cytokine. IL-6 signaling has been associated with stimulation of hypertrophic muscle growth and myogenesis through regulation of the proliferative capacity of muscle stem cells. Additional beneficial effects of IL-6 include regulation of energy metabolism, which is related to the capacity of actively contracting muscle to synthesize and release IL-6. Paradoxically, deleterious actions for IL-6 have also been proposed, such as promotion of atrophy and muscle wasting. We review the current evidence for these apparently contradictory effects, the mechanisms involved and discuss their possible biological implications.
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TL;DR: Interleukin-6 (IL-6), one of the major cytokines in the tumour microenvironment, is an important factor which is found at high concentrations and known to be deregulated in cancer.
Abstract: In the last several decades, the number of people dying from cancer-related deaths has not reduced significantly despite phenomenal advances in the technologies related to diagnosis and therapeutic modalities The principal cause behind limitations in the curability of this disease is the reducing sensitivity of the cancer cells towards conventional anticancer therapeutic modalities, particularly in advance stages of the disease Amongst several reasons, certain secretory factors released by the tumour cells into the microenvironment have been found to confer resistance towards chemo- and radiotherapy, besides promoting growth Interleukin-6 (IL-6), one of the major cytokines in the tumour microenvironment, is an important factor which is found at high concentrations and known to be deregulated in cancer Its overexpression has been reported in almost all types of tumours The strong association between inflammation and cancer is reflected by the high IL-6 levels in the tumour microenvironment, where it promotes tumorigenesis by regulating all hallmarks of cancer and multiple signalling pathways, including apoptosis, survival, proliferation, angiogenesis, invasiveness and metastasis, and, most importantly, the metabolism Moreover, IL-6 protects the cancer cells from therapy-induced DNA damage, oxidative stress and apoptosis by facilitating the repair and induction of countersignalling (antioxidant and anti-apoptotic/pro-survival) pathways Therefore, blocking IL-6 or inhibiting its associated signalling independently or in combination with conventional anticancer therapies could be a potential therapeutic strategy for the treatment of cancers with IL-6-dominated signalling
645 citations
Cites background from "Interleukin-6 myokine signaling in ..."
...Exercise is an important stimulus for increased gene expression and production of IL-6 in skeletal muscle, and the majority of circulating IL-6 during exercise originates from contracting muscle, resulting in a 100-fold increase over the normal physiological level [50, 54]....
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TL;DR: Persistent inflammation is involved in the pathogenesis of chronic diseases such as type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD).
Abstract: Background
Persistent inflammation is involved in the pathogenesis of chronic diseases such as type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD).
Aims
The aim of this review was to provide the reader with an update of the mechanisms whereby exercise-induced cytokines may impact cardiometabolic diseases.
Results
Evidence exists that interleukin (IL)-1β is involved in pancreatic β-cell damage, whereas TNF-α is a key molecule in peripheral insulin resistance. In addition, TNF-α appears to be involved in the pathogenesis of atherosclerosis and heart failure. A marked increase in IL-6 and IL-10 is provoked by exercise and exerts direct anti-inflammatory effects by an inhibition of TNF-α and by stimulating IL-1ra, thereby limiting IL-1β signalling. Moreover, muscle-derived IL-6 appears to have direct anti-inflammatory effects and serves as a mechanism to improve glucose tolerance. In addition, indirect anti-inflammatory effects of long-term exercise are mediated via improvements in body composition.
Conclusion
Physical activity represents a natural, strong anti-inflammatory strategy with minor side effects and should be integrated in the management of patients with cardiometabolic diseases.
387 citations
TL;DR: While macrophages lead similar processes in response to tissue injury in these tissues, their priorities and the consequences of their activities differ among tissues, and continuous injury and/or failed resolution of inflammation leads to chronic ailments in which macrophage activities may become detrimental.
Abstract: Tissue injury triggers a complex series of cellular responses, starting from inflammation activated by tissue and cell damage and proceeding to healing. By clearing cell debris, activating and resolving inflammation and promoting fibrosis, macrophages play key roles in most, if not all, phases of the response to injury. Recent studies of the mechanisms underlying the initial inflammation and later tissue regeneration and repair revealed that macrophages bridge these processes in part by supporting and activating stem/progenitor cells, clearing damaged tissue, remodeling extracellular matrix to prepare scaffolding for regeneration and promoting angiogenesis. However, macrophages also have a central role in the development of pathology induced by failed resolution (e.g. chronic inflammation) and excessive scarring. In this review, we summarize the activities of macrophages in inflammation and healing in response to acute injury in tissues with differing regenerative capacities. While macrophages lead similar processes in response to tissue injury in these tissues, their priorities and the consequences of their activities differ among tissues. Moreover, the magnitude, nature and duration of injury also greatly affect cellular responses and healing processes. In particular, continuous injury and/or failed resolution of inflammation leads to chronic ailments in which macrophage activities may become detrimental.
355 citations
TL;DR: Current knowledge of the role of acute and chronic psychosocial stress on low-grade inflammation in humans is summarized and potential relationships between inflammatory responses to acute psychossocial stress and long-term development of disease are discussed.
Abstract: Psychosocial stress is an important precursor of disease and reduced quality of life in humans. The biological pathways between stress exposure and pathophysiological processes underlying disease have received substantial scientific attention, although the roles of the hypothalamic-pituitary-adrenal axis and sympathetic nervous system remain insufficiently understood. Recent attention has focused on chronic systemic low-grade inflammation as a promising pathway because elevated inflammation often accompanies chronic psychosocial distress. These alterations of inflammatory activity play a key role in the pathophysiology of diseases that are adversely affected by chronic distress, such as cardiovascular disease. Transient increases in systemic inflammation are observed in response to acute psychosocial stress, with larger responses among individuals reporting adverse psychosocial states or conditions such as depression, lower self-esteem, or lower self-compassion. Recent evidence shows that lower subjective social status and perceived purpose in life are associated with sensitization of inflammatory stress responses to repeated stress exposure. The aims of this selective review article are to summarize current knowledge of the role of acute and chronic psychosocial stress on low-grade inflammation in humans and to discuss potential relationships between inflammatory responses to acute psychosocial stress and long-term development of disease.
352 citations
TL;DR: How exercise disrupts the vicious cycle of chronic inflammation directly, after each bout of exercise, and indirectly, by improving comorbidities and cardiovascular risk factors is discussed.
Abstract: Persistent systemic inflammation, a typical feature of inflammatory rheumatic diseases, is associated with a high cardiovascular risk and predisposes to metabolic disorders and muscle wasting. These disorders can lead to disability and decreased physical activity, exacerbating inflammation and the development of a network of chronic diseases, thus establishing a 'vicious cycle' of chronic inflammation. During the past two decades, advances in research have shed light on the role of exercise as a therapy for rheumatic diseases. One of the most important of these advances is the discovery that skeletal muscle communicates with other organs by secreting proteins called myokines. Some myokines are thought to induce anti-inflammatory responses with each bout of exercise and mediate long-term exercise-induced improvements in cardiovascular risk factors, having an indirect anti-inflammatory effect. Therefore, contrary to fears that physical activity might aggravate inflammatory pathways, exercise is now believed to be a potential treatment for patients with rheumatic diseases. In this Review, we discuss how exercise disrupts the vicious cycle of chronic inflammation directly, after each bout of exercise, and indirectly, by improving comorbidities and cardiovascular risk factors. We also discuss the mechanisms by which some myokines have anti-inflammatory functions in inflammatory rheumatic diseases.
332 citations
References
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TL;DR: The finding that the muscle secretome consists of several hundred secreted peptides provides a conceptual basis and a whole new paradigm for understanding how muscles communicate with other organs, such as adipose tissue, liver, pancreas, bones and brain.
Abstract: During the past decade, skeletal muscle has been identified as a secretory organ. Accordingly, we have suggested that cytokines and other peptides that are produced, expressed and released by muscle fibres and exert either autocrine, paracrine or endocrine effects should be classified as myokines. The finding that the muscle secretome consists of several hundred secreted peptides provides a conceptual basis and a whole new paradigm for understanding how muscles communicate with other organs, such as adipose tissue, liver, pancreas, bones and brain. However, some myokines exert their effects within the muscle itself. Thus, myostatin, LIF, IL-6 and IL-7 are involved in muscle hypertrophy and myogenesis, whereas BDNF and IL-6 are involved in AMPK-mediated fat oxidation. IL-6 also appears to have systemic effects on the liver, adipose tissue and the immune system, and mediates crosstalk between intestinal L cells and pancreatic islets. Other myokines include the osteogenic factors IGF-1 and FGF-2; FSTL-1, which improves the endothelial function of the vascular system; and the PGC-1α-dependent myokine irisin, which drives brown-fat-like development. Studies in the past few years suggest the existence of yet unidentified factors, secreted from muscle cells, which may influence cancer cell growth and pancreas function. Many proteins produced by skeletal muscle are dependent upon contraction; therefore, physical inactivity probably leads to an altered myokine response, which could provide a potential mechanism for the association between sedentary behaviour and many chronic diseases.
2,002 citations
TL;DR: This review focuses on the myokine IL-6, its regulation by exercise, its signaling pathways in skeletal muscle, and its role in metabolism in both health and disease.
Abstract: Skeletal muscle has recently been identified as an endocrine organ. It has, therefore, been suggested that cytokines and other peptides that are produced, expressed, and released by muscle fibers and exert paracrine, autocrine, or endocrine effects should be classified as "myokines." Recent research demonstrates that skeletal muscles can produce and express cytokines belonging to distinctly different families. However, the first identified and most studied myokine is the gp130 receptor cytokine interleukin-6 (IL-6). IL-6 was discovered as a myokine because of the observation that it increases up to 100-fold in the circulation during physical exercise. Identification of IL-6 production by skeletal muscle during physical activity generated renewed interest in the metabolic role of IL-6 because it created a paradox. On one hand, IL-6 is markedly produced and released in the postexercise period when insulin action is enhanced but, on the other hand, IL-6 has been associated with obesity and reduced insulin action. This review focuses on the myokine IL-6, its regulation by exercise, its signaling pathways in skeletal muscle, and its role in metabolism in both health and disease.
1,793 citations
TL;DR: It is concluded that IL-6 production induced by injury or infection is an important in vivo SOS signal which coordinates activities of liver cells, macrophages and lymphocytes.
Abstract: Interleukin-6 (IL-6) is a multifunctional cytokine that regulates various aspects of the immune response, acute-phase reaction and haematopoiesis (for reviews see refs 1, 2). In vitro, leukaemia inhibitory factor, oncostatin M, ciliary neurotrophic factor and interleukin-11 display overlapping activities with IL-6. This functional redundancy may be explained by the interactions of specific binding receptors with a common signal-transducing receptor (gp130) (for reviews see refs 3, 4). To elucidate the unique function of IL-6 in vivo, we have disrupted the IL-6 gene by homologous recombination. IL-6-deficient mice develop normally. They fail to control efficiently vaccinia virus and infection with Listeria monocytogenes, a facultative intracellular bacterium. The T-cell-dependent antibody response against vesicular stomatitis virus is impaired. Further, the inflammatory acute-phase response after tissue damage or infection is severely compromised, whereas it is only moderately affected after challenge with lipopolysaccharide. We conclude that IL-6 production induced by injury or infection is an important in vivo SOS signal which coordinates activities of liver cells, macrophages and lymphocytes.
1,780 citations
TL;DR: In addition to their roles in IGF transport, the six IGF-binding proteins (IGFBPs) regulate cell activity in various ways and manipulation of IGFBP-regulated pathways is speculated to offer therapeutic opportunities in cancer and other diseases.
Abstract: In addition to their roles in IGF transport, the six IGF-binding proteins (IGFBPs) regulate cell activity in various ways. By sequestering IGFs away from the type I IGF receptor, they may inhibit mitogenesis, differentiation, survival, and other IGF-stimulated events. IGFBP proteolysis can reverse this inhibition or generate IGFBP fragments with novel bioactivity. Alternatively, IGFBP interaction with cell or matrix components may concentrate IGFs near their receptor, enhancing IGF activity. IGF receptor-independent IGFBP actions are also increasingly recognized. IGFBP-1 interacts with alpha(5)beta(1) integrin, influencing cell adhesion and migration. IGFBP-2, -3, -5, and -6 have heparin-binding domains and can bind glycosaminoglycans. IGFBP-3 and -5 have carboxyl-terminal basic motifs incorporating heparin-binding and additional basic residues that interact with the cell surface and matrix, the nuclear transporter importin-beta, and other proteins. Serine/threonine kinase receptors are proposed for IGFBP-3 and -5, but their signaling functions are poorly understood. Other cell surface IGFBP-interacting proteins are uncharacterized as functional receptors. However, IGFBP-3 binds and modulates the retinoid X receptor-alpha, interacts with TGFbeta signaling through Smad proteins, and influences other signaling pathways. These interactions can modulate cell cycle and apoptosis. Because IGFBPs regulate cell functions by diverse mechanisms, manipulation of IGFBP-regulated pathways is speculated to offer therapeutic opportunities in cancer and other diseases.
1,737 citations
TL;DR: For the last half century, the advance of molecular biology, cell biology, and genetics has greatly improved the understanding of skeletal muscle biology, with focuses on functions of satellite cells and their niche during the process ofletal muscle regeneration.
Abstract: Adult skeletal muscle in mammals is a stable tissue under normal circumstances but has remarkable ability to repair after injury. Skeletal muscle regeneration is a highly orchestrated process invol...
1,585 citations