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Cited by 154Cytokine Signaling Pathways and InteractionsExercise and Physiological ResponsesAdipokines, Inflammation, and Metabolic Diseases

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Role of Interleukin-6 in Vascular Health and Disease

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Villar-Fincheira, Paulina, Sanhueza-Olivares, Fernanda, Norambuena-Soto, Ignacio, Cancino-Arenas, Nicole, Hernandez-Vargas, Felipe, Troncoso, Rodrigo, Gabrielli, Luigi, Chiong, Mario·2021·Frontiers in Molecular Biosciences
DOI 10.3389/fmolb.2021.641734PMC PMC8004548
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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.

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FIGURE 1 Interleukin-6 classical and trans-signaling. In the classical signaling, interleukin-6 (IL-6) binds to a membrane bound-IL-6 receptor (IL-6R) triggering the attachment and dimerization of glycoprotein 130 (gp130), followed by the activation of the non-receptor tyrosine kinase JAK that phosphorylates the STAT transcription factors. The activation of non-canonical signaling pathways, such as SHP-2/ERK, was also described. In the trans-signaling, soluble IL-6R (sIL-6R) was produced by shedding of the membrane bound IL-6R by ADAM10 or ADAM17. In human, but not in mice, sIL-6R was also produced by alternative splicing. IL-6 interacts with sIL-6R and the IL-6/sIL-6R complex binds a membrane bound gp130, activating the same signaling pathway described for classical signaling. Soluble gp130 (sgp130) was produced mainly by alternative splicing and also by shedding of the membrane bound gp130 by ADAM17 and A disintegrin. sgp130 binds the IL-6/sIL-6R complex and selectively inhibits the trans-signaling without affecting the classical signaling. Negative feedback involves the Stat-dependent expression of SOCS1/2 that inhibit JAK activity. Membrane bound IL-6 was described in hepatocytes and immune cells. Membrane bound gp130 is ubiquitous expressed in all cells.
FIGURE 1 Interleukin-6 classical and trans-signaling. In the classical signaling, interleukin-6 (IL-6) binds to a membrane bound-IL-6 receptor (IL-6R) triggering the attachment and dimerization of glycoprotein 130 (gp130), followed by the activation of the non-receptor tyrosine kinase JAK that phosphorylates the STAT transcription factors. The activation of non-canonical signaling pathways, such as SHP-2/ERK, was also described. In the trans-signaling, soluble IL-6R (sIL-6R) was produced by shedding of the membrane bound IL-6R by ADAM10 or ADAM17. In human, but not in mice, sIL-6R was also produced by alternative splicing. IL-6 interacts with sIL-6R and the IL-6/sIL-6R complex binds a membrane bound gp130, activating the same signaling pathway described for classical signaling. Soluble gp130 (sgp130) was produced mainly by alternative splicing and also by shedding of the membrane bound gp130 by ADAM17 and A disintegrin. sgp130 binds the IL-6/sIL-6R complex and selectively inhibits the trans-signaling without affecting the classical signaling. Negative feedback involves the Stat-dependent expression of SOCS1/2 that inhibit JAK activity. Membrane bound IL-6 was described in hepatocytes and immune cells. Membrane bound gp130 is ubiquitous expressed in all cells.CC BY · PubMed Central
FIGURE 2 IL-6 signaling in vascular remodeling induced by exercise. High intensity and long duration exercises induce a large plasma level increase of interleukin-6 (IL-6), and a modest increase in soluble IL-6 receptor (sIL-6R) and soluble glycoprotein 130 (sgp130). However, basal levels of sIL-6R and spg130 are at least hundred times higher than those of IL-6. IL-6 activates classical signaling, whereas the complex IL-6/sIL-6R activates trans-signaling. Trans-signaling is specifically regulated by sgp130. The role of IL-6 signaling and trans-signaling in vascular remodeling induced by exercise is unknown.
FIGURE 2 IL-6 signaling in vascular remodeling induced by exercise. High intensity and long duration exercises induce a large plasma level increase of interleukin-6 (IL-6), and a modest increase in soluble IL-6 receptor (sIL-6R) and soluble glycoprotein 130 (sgp130). However, basal levels of sIL-6R and spg130 are at least hundred times higher than those of IL-6. IL-6 activates classical signaling, whereas the complex IL-6/sIL-6R activates trans-signaling. Trans-signaling is specifically regulated by sgp130. The role of IL-6 signaling and trans-signaling in vascular remodeling induced by exercise is unknown.CC BY · PubMed Central

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  1. Croisier, 1999, Effects of training on exercise-induced muscle damage and interleukin 6 production, Muscle Nerve, 22, 208, 10.1002/(sici)1097-459810.1002/(sici)1097-4598(199902)22:2<208:aid-mus8>3.0.co;2-b · DOI

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Authors
Villar-Fincheira, P., Sanhueza-Olivares, F., Norambuena-Soto, I., Cancino-Arenas, N., Hernandez-Vargas, F., Troncoso, R., Gabrielli, L., & Chiong, M.
Affiliations
  • Advanced Center for Chronic Diseases (CL)
  • University of Chile (CL)
  • Pontificia Universidad Católica de Chile (CL)
Corresponding author
  • Gabrielli, Luigi
  • Chiong, Mario
ORCID
Venue
Frontiers in Molecular Biosciences
Publisher
Frontiers Media SA
Published
2021-03-16
Volume
8
Pages
641734-641734
ISSN
2296-889X (ISSN-L)
DOI
10.3389/fmolb.2021.641734
PMC
PMC8004548
OpenAlex
W3139260880
Cited by
154
References
154
Citations by year
2026: 20 · 2025: 39 · 2024: 32 · 2023: 35 · 2022: 19 · 2021: 9
FWCI
2.88
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Molecular Biosciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Universidad de Chile (submittedVersion, cc-by-nc-nd)
Funders
Fondo de Financiamiento de Centros de Investigación en Áreas Prioritarias (1170963, 15130011)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
  • Health Sciences › Medicine › Physiology (medical) › Exercise and Physiological Responses
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
Keywords
interleukin-6, vascular health, vascular disease, atherosclerosis, chronic inflammation, autoimmunity, physical activity, myokines, IL-6 signaling, trans-signaling, soluble IL-6 receptor, gp130, adipose tissue lipogenesis, vascular remodeling, innate and adaptive immunity

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