interleukin-6 (IL-6)

see also:

• immunology
• inflammation
• CRP - science and pathophysiology

• IL-6 is an important mediator of the acute phase immune response acting as an immediate warning and systemic activation mechanism and acts as a bridge between the innate and adaptive immune systems, activating both.
• in particular it appears to have a critical role in viral infections such as influenza¹⁾
  • in severe COVID-19 coronavirus (2019-nCoV / SARS-CoV-2), IL-6 levels appear to correlate with need for mechanical ventilation and, given that IL-6 is most likely mainly being produced from injured lung tissue in this condition, the correlation makes sense. It is likely that excessive levels of IL-6 may be a major contributor to cytokine storm in these patients. ²⁾
• the existence of soluble factors for the enhancement of IgG and IgE Ab responses was reported in 1973
• IL-6 gene was cloned in 1986
• IL-6 receptor cloned in 1988
• 1992, it was recognised that Gp130 is a common signal transducer for IL-6 family cytokine
• the whole picture of the IL-6 signaling system was completed in the early 1990s
• the pathological involvement of IL-6 in various diseases was also established by 1989
• IL-6 knockout mice have increased susceptibility to infection, display defective hepatic regeneration, a diminished acute phase response, altered body weight regulation, and a resistance to antigen-induced experimental arthritis
• it was found that if free serum concentration of tocilizumab (an IL-6 blocker) is maintained at more than 1 µg/ml, CRP remains negative demonstrating the major role in CRP production

• those who carry variants of IL-6 gene which reduce IL-6 effects have lower levels of C reactive protein (CRP), lower risk of cardiovascular disease, stroke, peripheral vascular disease (PVD or PAD), pneumonia and sepsis ³⁾

• its expression is strictly controlled by transcriptional and posttranscriptional mechanisms
• it is synthesized in a local lesion in the initial stage of inflammation and then is transported through the blood to the liver
• immune-mediated cells, mesenchymal cells, endothelial cells, fibroblasts, and many other cells are involved in the production of IL-6 in response to various stimuli
• the signature of exogenous pathogens, known as pathogen-associated molecular patterns, is recognized in the infected lesion by pathogen-recognition receptors (PRRs) of immune cells such as monocytes and macrophages
  • These PRRs comprise Toll-like receptors (TLRs), retinoic acid-inducible gene-1-like receptors, nucleotide-binding oligomerization domain-like receptors, and DNA receptors.
  • They stimulate a range of signaling pathways including NF-κB, and enhance the transcription of the mRNA of inflammatory cytokines such as IL-6, tumor necrosis factor (TNF)-α, and IL-1β.
  • TNF-α and IL-1β then activate transcription factors to produce IL-6.⁴⁾
• Damage-associated molecular patterns (DAMPs), which are released from damaged or dying cells in noninfectious inflammations such as burn or trauma, directly or indirectly promote inflammation.
  • during sterile surgical operations, an increase in serum IL-6 levels precedes elevation of body temperature and serum acute phase protein concentration
  • DAMPs from injured cells contain a variety of molecules such as mitochondrial (mt) DNA, high mobility group box 1 (HMGB1), and S100 proteins
  • serum mtDNA levels in trauma patients are thousands of times higher than in controls and this elevation leads to TLR9 stimulation and NF-κB activation
  • binding of HMGB1 to TLR2, TLR4, and the receptor of advanced glycation end products (RAGE) can promote inflammation
  • the S100 family of proteins comprises more than 25 members, some of which also interact with RAGE to evoke sterile inflammation
• IL-6 production by skeletal muscle during exercise as a “myokine”
  • in resting muscle, the IL-6 gene is silent, but it is rapidly activated by contractions when the transcription rate is very fast and the fold changes of IL-6 mRNA is marked
  • IL-6 is released from working muscles into the circulation in high amounts modulated by the glycogen content in muscles and thus works as an energy sensor
  • IL-6 exerts its effect on adipose tissue, inducing lipolysis and gene transcription in abdominal subcutaneous fat and increases whole body lipid oxidation
  • IL-6 inhibits low-grade TNF-alpha-production and may thereby inhibit TNF-alpha-induced insulin resistance and atherosclerosis development

• “classic signalling” membrane bound IL-6 receptor (IL-6R)
  • only found on hepatocytes, some leukocytes and endothelial cells
  • acts on the membrane signal-transducing receptor subunit gp130 to activate the intracellular JAK-STAT (Janus kinase signal transducer and activator of transcription) pathway
• “trans-signaling” via sIL-6R (soluble IL-6R)
  • when IL-6 binds to sIL-6R the complex can then bind to Gp130 which is present on all cells to activate the intracellular JAK-STAT (Janus kinase signal transducer and activator of transcription) pathway
• “trans-presentation”

• stimulates production of hepatic acute phase reactants such as:
  • CRP production in hepatocytes
  • serum amyloid A (SAA)
  • haptoglobin
  • α1-antichymotrypsin
• reduces the hepatic production of fibronectin, albumin, and transferrin
• involved in the regulation of serum iron and zinc levels via control of their transporters:
  • induces hepcidin production, which blocks the action of iron transporter ferroportin 1 on gut and, thus, reduces serum iron levels and can cause the anaemia of chronic inflammation
  • enhances zinc importer ZIP14 expression on hepatocytes and so induces hypozincemia seen in inflammation
• in the bone marrow, it promotes megakaryocyte maturation, thus leading to the release of platelets causing thrombocytosis
• promotes specific differentiation of naïve CD4+ T cells, thus performing an important function in the linking of innate to acquired immune response
  • IL-6, in combination with transforming growth factor (TGF)-β, is indispensable for Th17 differentiation from naïve CD4+ T cells
  • IL-6 inhibits TGF-β-induced Treg differentiation
  • Up-regulation of the Th17/Treg balance is considered to be responsible for the disruption of immunological tolerance, and is thus pathologically involved in the development of autoimmune and chronic inflammatory diseases
  • Th17 are important for the defense against pathogens at mucosal sites
• synergic interactions with IL-7 and IL-15 induce the differentiation and cytolytic capacity of CD8 T cells
• inhibits of Th1 polarization:
  • stimulates CD4 T cells to secrete IL-4 and direct the response to Th2
  • affects the secretion of IFNγ by CD4 T cells, an essential interferon to promote Th1 polarization.
  • inhibition of IFNγ secretion in Th1 cells affects CD8 T cell activation
• promotes T-follicular helper-cell differentiation
• increases production of IL-21 which regulates immunoglobulin (Ig) synthesis and IgG4 production in particular
• induces the differentiation of CD8+ T cells into cytotoxic T cells
• induces the differentiation of activated B cells into Ab-producing plasma cells,
  • continuous oversynthesis of IL-6 results in hypergammaglobulinemia and autoantibody production
• when IL-6 is generated in bone marrow stromal cells, it stimulates the RANKL which is indispensable for the differentiation and activation of osteoclasts and this leads to bone resorption and osteoporosis
• IL-6 also induces excess production of VEGF, leading to enhanced angiogenesis and increased vascular permeability, which are pathological features of inflammatory lesions and are seen in, for example, synovial tissues of rheumatoid arthritis or edema of remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome
• aids keratinocyte proliferation or the generation of collagen in dermal fibroblasts that may account for changes in the skin of patients with systemic sclerosis
• induces tissue factor surface expression on monocytes accompanied by enhanced monocyte procoagulant activity
• induction of PAI-1 (plasminogen activator inhibitor type 1) as part of the acute phase response
• inverse regulation of antithrombin and protein S leading to prothrombotic state
• upregulate cell adhesion molecules
• potentiate vascular permeability of endothelial cell walls leading to sustained loss of endothelial barrier function
• a potent pyrogenic cytokine, and has an essential role organizing lymphocyte trafficking to lymphoid organs during febrile events
• may cause hyponatraemia and hyperthyroidism ⁵⁾
• may play a key role in cytokine storm

• dysregulation of IL-6 production appears to have a key role in many chronic inflammatory conditions such as:
  • rheumatoid arthritis
    • a polymorphism at position -174 of the IL-6 promoter region is reportedly associated with systemic onset juvenile idiopathic arthritis and susceptibility to rheumatoid arthritis in Europeans
  • systemic lupus erythematosus (SLE)
  • scleroderma
  • inflammatory myopathies
  • Castleman’s disease
  • multiple myeloma
  • large vessel vasculitis
  • atherosclerosis
    • the increase in risk per SD of inflammation measured either by hsCRP (high-sensitivity C-reactive protein) or IL-6 consistently exceeded that of a 1-SD increase in cholesterol or blood pressure
• both hsCRP and IL-6 have long been shown to predict poor outcomes in acute coronary ischemia and in chronic secondary prevention
• IL-6 levels are locally increased at the site of atherosclerotic plaque rupture
• IL-6 levels also serve as a marker for early graft occlusion in patients undergoing CABG
• in a study of ST-segment–elevation myocardial infarction patients, circulating levels of sIL-6R were also found to associate with future vascular events and cardiovascular mortality

• elevated IL-6 levels have been shown to correlate with risk of uterine cancer ⁶⁾
  • missense IL6 receptor variant Asp358Ala is associated with increased conversion of membrane IL-6 receptor to soluble IL-6 receptor, thereby leading to downregulation of IL-6 classical signaling and upregulation of trans-signaling
  • trans-signaling of IL-6 on endothelial and smooth cells increases the secretion of monocyte chemoattractant protein 1 (MCP-1), a significant risk factor for endometrial cancer
  • IL-6 also promotes tumor growth in a paracrine manner by increasing aromatase expression and estrogen production in the surrounding stromal cells

• “Most people with cancer die of cachexia instead of cancer. And once the patient enters this stage, there's no way to go back because essentially there's no treatment.”
• blocking IL-6 from binding to neurons in a part of the brain called the area postrema (AP) prevents cachexia in mice, this worked by either:⁷⁾
  • neutralized IL-6 with custom antibodies
  • using CRISPR to reduce the levels of IL-6 receptors in AP neurons

• inhibitor effects can be obtained via:
  • inhibiting IL-6 production
  • direct blocking of IL-6 molecule
  • blocking of IL-6 receptor
  • blocking of sIL-6 receptor
  • blocking of IL-6 trans-presentation
  • blocking of Gp130
  • targeting of downstream kinase or transcription factors in the JAK-STAT (Janus kinase signal transducer and activator of transcription) pathway
• sirukumab and siltuximab
  • monoclonal antibody directed against the IL-6 ligand and block classic signaling (through the membrane-bound IL-6R) and trans-signaling (through the sIL6R)
• tocilizumab
  • a humanized anti-IL-6R monoclonal Ab of the IgG1 class
  • blocks IL-6-mediated signal transduction by inhibiting IL-6 binding to transmembrane and soluble IL-6R, blocks all 3 kinds of IL-6 signaling
  • used to Rx moderate-to-severe active rheumatoid arthritis and has outstanding efficacy for systemic juvenile idiopathic arthritis
• ziltivekimab
  • a fully human monoclonal antibody directed against the IL-6 ligand
  • is being studied to reduce atherosclerosis in those with chronic renal failure as it gives a dose-dependent substantive reduction in inflammatory markers such as C reactive protein (CRP) ⁸⁾
• baricitinib
  • JAK1/JAK2 inhibitor used to Rx psoriasis