Abstract
IL-6 is usually described as a pleiotropic cytokine produced in response to tissue injury or infection. As a pro-inflammatory cytokine, IL-6 activates innate and adaptative immune responses. IL-6 is released in the innate immune response by leukocytes as well as stromal cells upon pattern recognition receptor activation. IL-6 then recruits immune cells and triggers B and T cell response. Dysregulated IL-6 activity is associated with pathologies involving chronic inflammation and autoimmunity, including atherosclerosis. However, IL-6 is also produced and released under beneficial conditions, such as exercise, where IL-6 is associated with the anti-inflammatory and metabolic effects coupled with physical adaptation to intense training. Exercise-associated IL-6 acts on adipose tissue to induce lipogenesis and on arteries to induce adaptative vascular remodeling. These divergent actions could be explained by complex signaling networks. Classical IL-6 signaling involves a membrane-bound IL-6 receptor and glycoprotein 130 (gp130), while trans-signaling relies on a soluble version of IL-6R (sIL-6R) and membrane-bound gp130. Trans-signaling, but not the classical pathway, is regulated by soluble gp130. In this review, we discuss the similarities and differences in IL-6 cytokine and myokine signaling to explain the differential and opposite effects of this protein during inflammation and exercise, with a special focus on the vascular system.
Highlights
Interleukin-6 (IL-6) is the principal member of the cytokine IL-6 superfamily (White and Stephens, 2011; Tanaka et al, 2014)
IL-6 triggers an anti-inflammatory response by inducing expression of anti-inflammatory factors such as IL-1ra (IL-1 receptor agonist) and IL-10 and Interleukin-6 and Vascular Remodeling reducing production of the pro-inflammatory cytokines TNFα and IL-1ß (Eckardt et al, 2014)
Trans-signaling in the central nervous system suppresses feeding and improves glycemic control, effects that seem to be enhanced in obese mice (Timper et al, 2017). Because both classical and trans-signaling activate the same transduction cascades downstream of gp130 ((Mihara et al, 2012; Tanaka et al, 2014; Rose-John, 2018), factors differentially involved in both pathways, such as IL-6 receptor (IL-6R), and sgp130, the kinetics and tissuespecific expression should be considered in this discussion
Summary
Interleukin-6 (IL-6) is the principal member of the cytokine IL-6 superfamily (White and Stephens, 2011; Tanaka et al, 2014). Because both classical and trans-signaling activate the same transduction cascades downstream of gp130 ((Mihara et al, 2012; Tanaka et al, 2014; Rose-John, 2018), factors differentially involved in both pathways, such as IL-6R, and sgp130, the kinetics and tissuespecific expression should be considered in this discussion. Most studies conducted to date have demonstrated increased plasma IL-6 levels in response to various types of acute exercise (Catoire and Kersten, 2015).
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