IL-6: An Important Signaling Molecule That Can Become Dysregulated

Interleukin-6 (IL-6) is a cytokine that is typically produced because of an infection or tissue damage. The tightly regulated synthesis of IL-6 leads to the production of acute phase proteins such as C-reactive protein (CRP), fibrinogen, and hepcidin in the liver that act as emergency stress signals to protect the body.1

IL-6 Is a Key Part of Immune Response

IL-6 plays an important homeostatic role as part of the body’s immune system by regulating B cells and T cells. It triggers B cells to produce antibodies in the germinal centers within the lymph nodes. IL-6 preferentially promotes the differentiation of immature T cells toward TH2 effector cells and away from regulatory T cells (Treg). This imbalance in T-cell distribution has been noted in the development of autoimmune and inflammatory diseases.1,2

During an inflammatory response, IL-6 stimulates hepatocytes to produce acute phase proteins that contribute to the body’s natural defenses. Inside the bone marrow, IL-6 plays an important role in the formation of platelet cells and the activation of hematopoietic cells. With the help of key cell signaling mediators, IL‑6 also promotes bone homeostasis and angiogenesis.1

Stimulatory effects of IL-6 can lead to collagen production by dermal fibroblasts, as well as growth of myeloma cells and mesangial cells. IL-6 is also a critical regulator of energy metabolism in the liver and the skeletal muscle, and it supports insulin to eliminate free glucose.1,3

 Graphic explaining the role that IL-6 plays inside the human body. IL-6 is one of the proteins that is elevated in patients with idiopathic multicentric Castleman disease and can drive a cytokine storm in their body.

Adapted from Tanaka and Kishimoto, 2014.1

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A Cytokine Storm Associated With Elevated IL-6 May Lead to iMCD

A cytokine storm is characterized by perpetual activation of lymphocytes and macrophages, resulting in the secretion of large quantities of multiple cytokines. One of the key mediators of cytokine storms is IL-6. Overproduction of IL-6 can trigger autoimmunity and chronic inflammation that can result in tissue damage and have long-term, harmful effects on health.4

Increased IL-6 signaling is the established driver of iMCD. In patients with iMCD, IL-6 levels are highly elevated during flare-ups and correlate with the intensity of symptoms observed in patients.4

Dysregulated IL-6 can increase the growth of B cells, vascular endothelial growth factor (VEGF) signaling and angiogenesis, production of helper T cells (TH), and synthesis of acute phase proteins that can lead to various systemic symptoms of iMCD. An IL-6–driven cytokine storm may lead to systemic inflammation, multicentric lymphadenopathy, cytopenia, and potentially fatal multiple organ dysfunction.5,6

The following graphic highlights the biological effects of increased IL-6 on various cell types.6

  • Graphic showing increased B-cell growth in people with idiopathic multicentric Castleman disease.

    Increased B cell growth

    Overgrowth of B cells and plasma cells

  • Graphic showing increased VEGF in people with idiopathic multicentric Castleman disease.

    Increased VEGF

  • Increased T helper cells (TH2 cells) in people with idiopathic multicentric Castleman disease.

    Increased TH2 cells

  • Graphic showing systemic symptoms like fever are observed in people with idiopathic multicentric Castleman disease.

    Systemic symptoms

  • Graphic showing increased size of lymph nodes, lymphoma, and myeloma in people with idiopathic multicentric Castleman disease.

    Increased size of lymph nodes, lymphoma, myeloma

  • storm-icon-07

    Formation of blood vessels

    Increased blood supply to tumor

  • Increased autoimmune reactions and increased autoantibodies to organs in people with idiopathic multicentric Castleman disease.

    Autoimmune reactions

    Increased autoantibodies to organs

  • Graphic showing inflammatory response, increased ESR, CRP, IgG, anemia, DVT in people with idiopathic multicentric Castleman disease.

    Inflammatory response

    Increased ESR, CRP, IgG, anemia, DVT

Graphic of a cytokine storm, which is common in people with idiopathic multicentric Castleman disease.

Did you know?

A cytokine storm may result from the dysregulated overproduction of cytokines such as IL-6 and may have severe or life-threatening consequences.7

Abbreviations: DVT, deep vein thrombosis; ESR, erythrocyte sedimentation rate; IgG, immunoglobulin G; TH2, type 2 helper T cells.
References:
  1. Tanaka T, Kishimoto T. The biology and medical implications of interleukin-6. Cancer Immunol Res. 2014;2(4):288-294.

  2. Stebegg M, Kumar SD, Silva-Cayetano A, Fonseca VR, Linterman MA, Graca L. Regulation of the germinal center response. Front Immunol. 2018;9:2469.

  3. Garbers C, Heink S, Korn T, Rose-John S. Interleukin-6: designing specific therapeutics for a complex cytokine. Nat Rev Drug Discov. 2018;17(6):395-412.

  4. England JT, Abdulla A, Biggs CM, et al. Weathering the COVID-19 storm: lessons from hematologic cytokine syndromes. Blood Rev. Published online May 15, 2020. doi:10.1016/j.blre.2020.100707

  5. Fajgenbaum DC. Novel insights and therapeutic approaches in idiopathic multicentric Castleman disease. Blood. 2018;132(22):2323-2330.

  6. van Rhee F, Stone K, Szmania S, Barlogie B, Singh Z. Castleman disease in the 21st century: an update on diagnosis, assessment, and therapy. Clin Adv Hematol Oncol. 2010;8(7):486-498.

  7. Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG. Into the eye of the cytokine storm. Microbiol Mol Biol Rev. 2012;76(1):16-32.

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