LECTURE SERIES - INTERLEUKIN 6 (IL6) 

Interleukin-6 | IL6

  • Alias: Interleukin-6, B-cell hybridoma growth factor, Hybridoma growth factor

  • IL-6 pleiotropic TH2 cytokine produced by a variety of cell types that include monocytes, fibroblasts, and endothelial cells. Upon stimulation, IL-6 is secreted by many additional cell types including macrophages, T cells, B cells, mast cells, glial cells, eosinophils, keratinocytes, and granulocytes.

  • IL-6 influences antigen-specific immune responses, inflammatory responses, it is a major mediator of the acute phase reaction and hematopoiesis, and plays a central role in host defense mechanisms. Furthermore, IL-6 is involved in B-cell differentiation, the induction of acute phase proteins in liver cells, growth promotion of myeloma/plasmacytoma/hybridoma cells, induction of IL-2 and IL-2R (CD25) expression, proliferation and differentiation of T cells, inhibition of cell growth of certain myeloid leukemic cell lines, and induction of their differentiation to macrophages.

  • The level of IL-6 has proven to be a very important biomarker. This includes proliferative diseases where elevated plasma levels of IL-6 are observed in patients with multiple myeloma, other B-cell dyscrasias, Lennert’s T lymphoma, Castleman’s disease, renal cell carcinoma, and various other solid tumors.

  • It is also an important biomarker in monitoring inflammatory responses were IL-6 is involved in the induction of acute phase proteins and induction of fever.

  • Elevated serum levels of IL-6 are also found in patients with inflammatory arthritis and traumatic arthritis

  • IL-6 is a cytokine with a wide variety of biological functions. It is a potent lymphoid cell growth factor that stimulates the growth and survivability of certain B cells and T cells. It plays an essential role in the final differentiation of b-cells into Ig-secreting cells, it induces myeloma and plasmacytoma growth, it induces nerve cells differentiation and in hepatocytes it induces acute phase reactants.

  • Cytokines Interleukin 6 (IL6) can increase up to a 1,000-fold during trauma and infection.

  • Chronic elevation of serum IL-6 is associated with the progression of atherosclerosis in patients with vascular risk factors.

  • Elevated IL-6 but not CRP in midlife predicts cognitive decline

  • Chronic lumbar radicular pain may be associated with a persistent increase of the pro-inflammatory substances IL-6 and IL-8 in serum after disc herniation.

  • Interleukin-6 (IL-6) is a growth and survival factor in human glioblastoma cells and plays an important role in malignant progression.

  • Its increased levels have been associated with elevated cancer risk, and also these levels have been found to be a prognostic factor for several cancer types.

  • In addition, increased levels have been found in coronary heart disease, insulin resistant patients, advance stage cancer patients, atopy/asthma and in patients with blood circulating micrometastasis.

Int J Antimicrob Agents​. 2020 Mar 29;105954. doi: 10.1016/j.ijantimicag.2020.105954. Online ahead of print.

The Cytokine Release Syndrome (CRS) of Severe COVID-19 and Interleukin-6 Receptor (IL-6R) Antagonist Tocilizumab May Be the Key to Reduce the Mortality

Chi Zhang 1Zhao Wu 1Jia-Wen Li 1Hong Zhao 2Gui-Qiang Wang 3

Abstract

Since December 2019, a viral pneumonia (COVID-19) from Wuhan, China has swept the world. Although the case fatality rate is not high, the number of people infected is large, and there are still a large number of patients dying. With the collation and publication of more and more clinical data, a large number of data suggest that there are mild or severe cytokine storms in severe patients, which is also an important cause of death. Therefore, the treatment of cytokine storm has become an important part of rescuing severe patients.

Interleukin-6 (IL-6) plays an important role in cytokine release syndrome (CRS). If it can block the signal transduction pathway of IL-6, it is expected to become a new method for the treatment of severe patients. Tocilizumab is a blocker of IL-6R, which can effectively block IL-6 signal transduction pathway. So, tocilizumab is likely to become an effective drug for patients with severe COVID-19.

Oncology​. 2020;98(3):131-137. doi: 10.1159/000505099. Epub 2020 Jan 20.

Interleukin-6: A Masterplayer in the Cytokine Network

Peter Uciechowski 1Wolfram C M Dempke 2

Abstract

Interleukin-6 (IL-6) is a member of the pro-inflammatory cytokine family, induces the expression of a variety of proteins responsible for acute inflammation, and plays an important role in the proliferation and differentiation of cells in humans. IL-6 signaling is mediated by building a complex of IL-6, the transmembrane IL-6 receptor (mIL-6R) or with soluble forms of IL-6R (sIL-6R), and the signal-transducing subunit molecule gp130. Therefore, three modes for IL-6 signaling may occur in which IL-6 is binding to mIL-6R (classic), to sIL-6R (trans-signaling), or is joined through IL-6R to gp130 on nearby located cells (trans-presentation). These pathways, and the fact that gp130 is ubiquitously expressed, lead to the pleiotropic functions of IL-6. The control of IL-6 signaling is regulated through the induction of suppressor molecules after activation of the IL-6 pathways as well as through the presence of sIL-6R and gp130 forms in the blood. Vice versa, an overproduction of IL-6 and dysregulation of the IL-6 signaling pathways can result in inflammatory and autoimmune disorders as well as cancer development suggesting that IL-6 plays a significant role in the human cytokine network. Several therapeutic agents have been evaluated for inhibiting the cytokine itself, the signaling via the IL-6 receptor, or target kinases (e.g., JAK/STAT) associated with the signaling pathways. Amongst others, tocilizumab (anti-IL-6R humanized antibody) has been approved for the treatment of rheumatoid arthritis, cytokine release syndrome, and idiopathic multicentric Castleman's disease (iMCD), whereas siltuximab (an IL-6 antagonist) received approval for iMCD only. Although not all IL-6-associated diseases respond to IL-6 blockade, a better understanding of the underlying mechanisms of the IL-6 pathways may, therefore, help to find the best treatment for IL-6-associated diseases in the near future.

J Autoimmun​. 2020 Apr 10;102452. doi: 10.1016/j.jaut.2020.102452. Online ahead of print.

Can We Use interleukin-6 (IL-6) Blockade for Coronavirus Disease 2019 (COVID-19)-induced Cytokine Release Syndrome (CRS)?

Bingwen Liu 1Min Li 2Zhiguang Zhou 1Xuan Guan 3Yufei Xiang 4

Abstract

The emergent outbreak of coronavirus disease 2019 (COVID-19) has caused a global pandemic. Acute respiratory distress syndrome (ARDS) and multiorgan dysfunction are among the leading causes of death in critically ill patients with COVID-19. The elevated inflammatory cytokines suggest that a cytokine storm, also known as cytokine release syndrome (CRS), may play a major role in the pathology of COVID-19. However, the efficacy of corticosteroids, commonly utilized antiinflammatory agents, to treat COVID-19-induced CRS is controversial. There is an urgent need for novel therapies to treat COVID-19-induced CRS. Here, we discuss the pathogenesis of severe acute respiratory syndrome (SARS)-induced CRS, compare the CRS in COVID-19 with that in SARS and Middle East respiratory syndrome (MERS), and summarize the existing therapies for CRS. We propose to utilize interleukin-6 (IL-6) blockade to manage COVID-19-induced CRS and discuss several factors that should be taken into consideration for its clinical application.

Association of interleukin-6 (rs1800796) but not transforming growth factor beta 1 (rs1800469) with serum calcium levels in osteoporotic patients.

Gene 2018 May 31. Epub 2018 May 31.

Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran; Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran; Genetic Laboratory, Amirkola Children's Hospital, Babol University of Medical Sciences, Babol, Iran. ​

Background: Osteoporosis is a multifactorial disease with a strong genetic influence. Recent studies have demonstrated that cytokines, such as TGF-β1 and interleukin 6 (IL-6) play complex roles in the normal bone metabolism and pathophysiology of osteoporosis. Here, we investigated the roles of 2 polymorphisms mapping to the promoters of TGF-β1and IL-6 genes on the genetic susceptibility to osteoporosis as well as calcium and vitamin D levels.


Methods: A cohort of 297 elderly participants in northern Iran comprising 181 osteoporotic patients (mean age ± SD, 68.36 ± 7.21 years) and 116 unrelated healthy controls (mean age ± SD, 64 ± 5.44 years) was studied for TGF-β1(C-509T) and IL-6 (G-634C) polymorphisms using PCR-RFLP method.

Results: A significant relationship was observed between calcium level and IL-6 genotypes in osteoporotic males (P = 0.011) and females (P = 0.020). No significant differences were observed between osteoporotic and control groups with respect to allele frequency or genotype distribution based on the 2 selected polymorphisms under different genetic models. The results remained the same after comparing the BMD values of either the femur neck or lumbar spine with the genotypes of the elderly men and women when analyzed separately.

Conclusion: IL-6 genotype influences serum calcium levels in osteoporotic patients. The lack of association between the common genetic variations of TGF-β1 and IL-6 genes, and BMD highlights the complex genetic background of osteoporosis in the north of Iran.

Accelerated subcutaneous nodulosis in patients with rheumatoid arthritis treated with tocilizumab: a case series.

J Med Case Rep 2018 Jun 3;12(1):154. Epub 2018 Jun 3.

Department of Rheumatology, ASST Fatebenefratelli-Sacco, via GB Grassi n. 74, 20157, Milan, Italy.

​Background: Tocilizumab is a monoclonal antibody directed against the interleukin-6 receptor, which is approved for the treatment of moderate-to-severe rheumatoid arthritis. Authors have found that it prevents lung and subcutaneous nodulosis in patients with rheumatoid arthritis but, to the best of our knowledge, there are no data concerning the acceleration of subcutaneous nodulosis during tocilizumab therapy.


Case Presentation: We report for the first time a small case series of five patients with rheumatoid arthritis: a 46-year-old white woman, a 70-year-old white woman, a 63-year-old white woman, a 69-year-old white man, and a 72-year-old white woman (mean age 64 ± 10.6 years); they experienced worsening subcutaneous nodulosis during treatment with intravenously administered tocilizumab. Four of the five patients were positive for rheumatoid factor and five for anti-citrullinated peptide antibodies. All of the patients had previously been treated with various conventional and biological drugs; at the time of our observation, three were taking methotrexate, two hydroxychloroquine, and four were taking prednisone. Tocilizumab 8 mg/kg was administered intravenously every 4 weeks for a mean of 43.4 ± 32.4 months, and led to good disease control in three cases. All of the patients had a history of subcutaneous nodulosis, which considerably worsened during tocilizumab treatment, with the development of new nodules on their fingers, elbows, or in the inframammary fold, tending to ulcerate. The management of this medical event included discontinuation of methotrexate, the administration of steroids, the addition of hydroxychloroquine or colchicine, the use of antibiotics, and surgery. However, neither pharmacological nor surgical treatment was completely effective, as the nodules tended to recur and increased in number and size.

Conclusions: To the best of our knowledge, this is the first report describing accelerated subcutaneous nodulosis in a small case series of patients with rheumatoid arthritis treated with tocilizumab.

Surg Case Rep. 2016 Dec;2(1):101. doi: 10.1186/s40792-016-0232-8. Epub 2016 Sep 23.

Complete resection for pleomorphic lung cancer with a high serum IL-6 level: a case report.

Oka S1, Matsumiya H2, Shinohara S2, Kuwata T2, Takenaka M2, Chikaishi Y2, Hirai A2, Imanishi N2, Kuroda K2, Uramoto H2, Tanaka F2.

Author information

Abstract

BACKGROUND:

Pleomorphic lung cancer cells have been reported to produce cytokines, resulting in systemic reactions. Recently, the autonomous production of hematopoietic cytokines (granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF], and interleukin-6 [IL-6]) was observed in some of these patients.

CASE PRESENTATION:

We herein report a case of complete resection of right pleomorphic lung cancer producing IL-6. The patient had a high-grade fever before surgery, and a blood examination showed high IL-6 and CRP levels in the serum. After surgery, the patient no longer had a fever, and the elevated serum IL-6 levels had dropped to values less than those before the operation. Immunohistochemically, the carcinoma cells were faintly or focally positive for IL-6 and negative for G-CSF.

CONCLUSIONS:

The symptoms in the present case were dramatically improved by surgery. In addition, an immunohistochemical examination showed that the cancer cells were positive for IL-6.

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