Inflammation Part 8: Interleukin 6

Interleukin-6 (IL-6)

Dicken Weatherby, N.D. and Beth Ellen DiLuglio, MS, RDN, LDN

The ODX Inflammation Series

1. Inflammation Part 1 - The Fire Inside - Overview
2. Inflammation Part 2 - The Fire Inside - "Inflammaging"
3. Inflammation Part 3 - A Focus on Cytokines
4. Inflammation Part 4 - Cytokines & Their Functions
5. Inflammation Part 5 - The Cytokine Storm
6. Inflammation Part 6 - Cytokine Biomarkers
7. Inflammation Part 7 - Establishing Cytokine Ranges
8. Inflammation Part 8 - Interleukin 6
9. Inflammation Part 9 - Interleukin 10
10. Inflammation Part 10 - The IL-6 : IL-10 Ratio
11. Inflammation Part 11 - Resolution & Intervention

Interleukin-6 is one of a number of compounds in the IL-6 family which includes IL-11, IL-27, IL-31, and other metabolically active compounds. [1] Several different cell types secrete IL-6 in response to pathological events and conditions including inflammation, infection, and cancer. Its expression is regulated by NF-IL-6, NF-kappa-B, and other activating nuclear factors. Bacterial LPS, viral infection, TNF-alpha, and IL-1 can all stimulate release IL-6 due to their activation of NF-kappa-B.[2]

Under normal circumstances, IL-6 is maintained at low levels in the blood but increases with age, frailty, and chronic disease and correlates with mortality. Genetic factors can contribute to increased levels of IL-6 associated with cognitive decline and mortality in those with vascular disease related to aging. [3]

IL-6 does exert both pro- and anti-inflammatory actions which must be considered and understood, depending on signaling pathways. During infection and inflammation, IL-6 promotes inflammatory actions by complexing with a specialized soluble receptor via trans-signaling.

However, it exerts anti-inflammatory actions via classic signaling, regulating regenerative processes and participating in bone homeostasis and neural functions. Recognition of the dual functions of IL-6 has prompted researchers to urge caution when developing drugs that block both classic and trans-signaling IL-6 actions. [4]

Recognition and consideration of IL-6’s regulatory role in maintaining body temperature, bone health, and brain function [5] further supports the call for targeted versus indiscriminate suppression of systemic IL-6 levels.

In its innate immune system role, IL-6 facilitates the acute phase response by stimulating hepatic synthesis of inflammatory compounds CRP, fibrinogen, and serum amyloid A. It also plays a key role in adaptive immunity, enhancing antibody response by stimulating proliferation of B cells. T cells, macrophages, and endothelial cells are all capable of producing IL-6. [6]

Elevations in IL-6 are common among age-related pathologies associated with inflammation and serum IL-6 is considered a marker of inflammation. [7]

Serum measurement of IL-6 is used to assess chronic inflammatory disorders and infections: [8] [9]

• Ankylosing spondylitis
• Autoimmune disorders
• Cardiovascular disease
• Certain cancers
• Diabetes
• Infection
• Inflammatory bowel disease
• Prosthetic joint infections (better diagnostic accuracy than WBCs, CRP, and ESR
• Sepsis (levels correlate with severity of sepsis)
• Stroke
• Systemic lupus erythematosus
• IL-6 may be measured in synovial fluid and cerebrospinal fluid for targeted assessment
• Rheumatoid arthritis (immunosuppressive drug Tocilizumab blocks IL-6)
  • Note that treatment with tocilizumab, which blocks both classic and trans IL-6 signaling, increases risk of bacterial infection. [10]

Serum IL-6 can provide clues to a number of conditions:

• Elevated serum IL-6 is an independent risk factor for cardiovascular disease and mortality. Chronic exposure to air pollution is associated with baseline elevations in IL-6, increasing overall risk of CVD .[11]
• Serum IL-6 is found to correlate significantly with circulating CRP. [12]
• Circulating IL-6 was significantly associated with elevations in blood pressure (systolic and diastolic), fasting insulin, and fasting insulin resistance index (FIRI) in seemingly healthy volunteers. Excluding smokers revealed a correlation of IL-6 with percent and absolute fat mass as well. Gender differences were revealed indicating that IL-6 was significantly associated with fasting insulin and FIRI in men but not significantly in women. The significant association of IL-6 with blood pressure was seen in women but not in men. [13]
• Smokers tend to have increased levels of pro-inflammatory IL-6 and decreased levels of anti-inflammatory IL-10. [14]
• Elevated IL-6 contributes to loss of appetite. [15]
• IL-6 can contribute to anemia by upregulating hepcidin, a peptide hormone that blocks iron uptake from the intestine. [16]
• IL-6, along with other members of the IL-6 family, is significantly upregulated in cancer, especially during tumorigenesis and metastasis. [17]
• Measurement of serum IL-6 can help gauge systemic cytokine response in sepsis as it is stimulated by TNF and IL-1 beta, early acute phase responders .[18]
• Elevations in IL-6, along with IL-1beta, and TNF-alpha, are observed in patients with coronavirus disease 2019 (COVID-19) at levels that correlate positively with severity of disease. [19]

Researchers warn against using IL-6 levels alone as a prognostic tool as levels can vary by time of day (a trough in the morning has been noted); variability between patients; presence of comorbidities such as obesity; pharmaceutical manipulation of levels; and variations in signaling which can determine whether IL-6 has pro- or anti-inflammatory effects. [20]

Standard ranges serum IL-6

Labcorp [21] - 0-13 pg/mL

Mayo Clinic [22] - 1.8 pg/mL or less

Labcorp statement for serum IL-6 assessment: [23]

“Based on the available clinical data, PCR-confirmed COVID-19 patients with IL-6 concentrations >35.0 pg/mL at presentation are at risk for mechanical ventilation during their hospitalization. IL-6 values should be used in conjunction with clinical findings and the results of other laboratory findings. IL-6 values alone are not indicative of the need for endotracheal intubation or mechanical ventilation.”

Various cutoffs have been proposed for IL-6: [24]

Next: Inflammation Part 9: Interleukin 10

Next Up: Inflammation Part 9 - A Focus on IL-6 & IL-10 - part 2

Research

[1] Scheller, Jürgen et al. “The pro- and anti-inflammatory properties of the cytokine interleukin-6.” Biochimica et biophysica acta vol. 1813,5 (2011): 878-88. 

[2] 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.

[3] Rea, Irene Maeve et al. “Age and Age-Related Diseases: Role of Inflammation Triggers and Cytokines.” Frontiers in immunology vol. 9 586. 9 Apr. 2018.

[4] Scheller, Jürgen et al. “The pro- and anti-inflammatory properties of the cytokine interleukin-6.” Biochimica et biophysica acta vol. 1813,5 (2011): 878-88. 

[5] Lab Tests Online. Interleukin-6. https://labtestsonline.org/tests/interleukin-6

[6] Mayo Clinic Interleukin-6, Plasma. https://www.mayocliniclabs.com/test-catalog/Clinical+and+Interpretive/63020

[7] Franceschi, Claudio, and Judith Campisi. “Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases.” The journals of gerontology. Series A, Biological sciences and medical sciences vol. 69 Suppl 1 (2014): S4-9. doi:10.1093/gerona/glu057 [R] [R]

[8] Mayo Clinic Interleukin-6, Plasma. https://www.mayocliniclabs.com/test-catalog/Clinical+and+Interpretive/63020

[9] Lab Tests Online. Interleukin-6. https://labtestsonline.org/tests/interleukin-6

[10] 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.

[11] Thompson, Aaron M S et al. “Baseline repeated measures from controlled human exposure studies: associations between ambient air pollution exposure and the systemic inflammatory biomarkers IL-6 and fibrinogen.” Environmental health perspectives vol. 118,1 (2010): 120-4. 

[12] Fernandez-Real, J M et al. “Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women.” The Journal of clinical endocrinology and metabolism vol. 86,3 (2001): 1154-9. 

[13] Fernandez-Real, J M et al. “Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women.” The Journal of clinical endocrinology and metabolism vol. 86,3 (2001): 1154-9.

[14] Roberto Carnevale, Vittoria Cammisotto, Francesca Pagano and Cristina Nocella (November 5th 2018). Effects of Smoking on Oxidative Stress and Vascular Function, Smoking Prevention and Cessation, Mirjana Rajer, IntechOpen.

[15] Mahan, L. Kathleen; Raymond, Janice L. Krause's Food & the Nutrition Care Process - E-Book (Krause's Food & Nutrition Therapy). Elsevier Health Sciences. Kindle Edition.

[16] Takahashi T, Maruoka H. [Blood cytokine levels as a clinical laboratory test]. Rinsho Byori. 2007 Mar;55(3):272-9.

[17] Taniguchi, Koji, and Michael Karin. “IL-6 and related cytokines as the critical lynchpins between inflammation and cancer.” Seminars in immunology vol. 26,1 (2014): 54-74. 

[18] Tisoncik, Jennifer R et al. “Into the eye of the cytokine storm.” Microbiology and molecular biology reviews : MMBR vol. 76,1 (2012): 16-32. 

[19] Young, Trevor K, and John G Zampella. “Supplements for COVID-19: A modifiable environmental risk.” Clinical immunology (Orlando, Fla.) vol. 216 (2020): 108465. 

[20] 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.

[21] Labcorp. Serum IL-6 https://www.labcorp.com/tests/140916/interleukin-6-serum

[22] Mayo Clinic. IL-6. https://www.mayocliniclabs.com/test-catalog/Clinical+and+Interpretive/63020

[23] Labcorp. Serum IL-6 https://www.labcorp.com/tests/140916/interleukin-6-serum

[24] 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.