Welcome to part 5 of the ODX Inflammation Series. In this post, the ODX Research Team reviews cytokines and the physiology and biochemistry of the cytokine storm.
Unbridled inflammation and the cytokine storm
Dicken Weatherby, N.D. and Beth Ellen DiLuglio, MS, RDN, LDN
The ODX Inflammation Series
- Inflammation Part 1 - The Fire Inside - Overview
- Inflammation Part 2 - The Fire Inside - "Inflammaging"
- Inflammation Part 3 - A Focus on Cytokines
- Inflammation Part 4 - Cytokines & Their Functions
- Inflammation Part 5 - The Cytokine Storm
- Inflammation Part 6 - Cytokine Biomarkers
- Inflammation Part 7 - Establishing Cytokine Ranges
- Inflammation Part 8 - Interleukin 6
- Inflammation Part 9 - Interleukin 10
- Inflammation Part 10 - The IL-6 : IL-10 Ratio
- Inflammation Part 11 - Resolution & Intervention
Resolution of inflammation is just as important as its initiation. Early inflammation can help fight pathogens and clear damaged tissue. However, prolonged inflammation can cause cellular damage leading to organ compromise.
Local inflammation can be beneficial as it increases temperature, facilitates blood flow, mobilizes white blood cells and plasma proteins, and sends warning pain signals to the brain. [1] Specific cytokines may be underlying factors in promoting persistent pathological pain. [2]
However, an uncontrolled prolonged systemic immune response can lead to a “cytokine storm,” recruitment of aggressive immune cells, and an inflammatory cascade that contributes to tissue and organ damage. [3]
Cytokine storm can have a wide variety of manifestations with cardiovascular, cutaneous, gastrointestinal, hematological, and neurological consequences. Its severity may be categorized as mild, moderate, severe, and life-threatening. [4]
Severe cytokine storm can be characterized by markedly elevated pro-inflammatory cytokines (interleukins, chemokines, interferons, and tumor necrosis factors). [5]
The cytokine storm and its manifestations have been observed in severe cases of coronavirus disease 2019 (COVID-19), the global pandemic that has taken millions of lives worldwide.
Both IL-6 and IL-10 can be elevated, reflecting the cytokine battle that rages in this devastating viral disease.
In one study of hospitalized COVID-19 patients, an IL-6 cutoff of 9.16 pg/mL was used to diagnose severe COVID-19. One patient with what were considered moderate symptoms upon admission had initial elevated IL-6 of 24.64 pg/mL, IL-10 of 25.66 pg/mL, and CRP of 19.3 mg/L. That patient died within 14 days of admission. [6]
Elevated pro-inflammatory cytokines correlate with acute respiratory distress syndrome (ARDS) in severe COVID-19. [7]
At the heart of the cytokine storm, you will see: [8]
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Cytokine
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Actions, functions
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Chemokines
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Control chemotaxis, recruitment of leukocytes, many are proinflammatory
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Colony-stimulating factors
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Stimulate hematopoietic progenitor cell proliferation and differentiation
Associated with inflammation, may work with IL-1 and TNF
Perpetuates inflammation by increasing cytokine-producing macrophages
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Interferons
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Regulate innate immune response to viruses and other pathogenic microorganisms
Stimulate production of proteins with anti-proliferative, antiviral, and immunomodulatory effects
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Interleukins
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Produced by wide variety of cells, not just leukocytes
Regulate growth and differentiation of leukocytes
Take part in acute phase response with local and systemic effects
May be pro- or anti-inflammatory
Pro-inflammatory IL-1 alpha and IL-1 beta direct immune cells to site of infection, activate epithelial cells, and stimulate secondary cytokine production.
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Tumor necrosis factors (TNFs)
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Proinflammatory, activates cytotoxic T lymphocytes
A central cytokine in acute viral illness
Produced by a wide variety of cells with potential for action on all cells (all cells appear to have TNF receptors)
Excess TNFs characteristic of chronic inflammation and autoimmune disorders
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Next Up: Inflammation Part 6 - A Focus on Cytokines - Cytokine Biomarkers
Research
[1] Tisoncik, Jennifer R et al. “Into the eye of the cytokine storm.” Microbiology and molecular biology reviews : MMBR vol. 76,1 (2012): 16-32.
[2] Zhang, Jun-Ming, and Jianxiong An. “Cytokines, inflammation, and pain.” International anesthesiology clinics vol. 45,2 (2007): 27-37.
[3] Young, Trevor K, and John G Zampella. “Supplements for COVID-19: A modifiable environmental risk.” Clinical immunology (Orlando, Fla.) vol. 216 (2020): 108465. doi:10.1016/j.clim.2020.108465
[4] Copaescu, Ana et al. “The role of IL-6 and other mediators in the cytokine storm associated with SARS-CoV-2 infection.” The Journal of allergy and clinical immunology vol. 146,3 (2020): 518-534.e1.
[5] Liu, Qiang et al. “The cytokine storm of severe influenza and development of immunomodulatory therapy.” Cellular & molecular immunology vol. 13,1 (2016): 3-10.
[6] Han, Huan, et al. "Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors." Emerging Microbes & Infections 9.1 (2020): 1123-1130.
[7] McElvaney, Oliver J et al. “A linear prognostic score based on the ratio of interleukin-6 to interleukin-10 predicts outcomes in COVID-19.” EBioMedicine, vol. 61 103026. 8 Oct. 2020.
[8] Tisoncik, Jennifer R et al. “Into the eye of the cytokine storm.” Microbiology and molecular biology reviews : MMBR vol. 76,1 (2012): 16-32.
