Uploaded byDr Sarath Krishnan M P
Interleukin 6
The document presents a case study on interleukin-6 (IL-6), detailing its role as a cytokine involved in inflammatory responses, particularly in COVID-19 where elevated levels are associated with severe disease outcomes. It describes IL-6's signaling pathways, production by various cells, and its implications in several autoimmune and chronic diseases. The study emphasizes that IL-6 acts as a biomarker for disease severity and discusses potential therapeutic approaches targeting IL-6 receptors in inflammatory conditions.
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Interleukin 6
- 1. Interleukin 6 Presenter: DrSarath Krishnan M P Junior Resident/Biochemistry AIIMS Rishikesh 1
- 2. ✘ Case study ✘Cytokines ✘ Interleukins ✘ IL-6 Function and Family ✘ IL-6 signalling pathway ✘ IL-6 and Covid 19 ✘ IL-6 and other diseases ✘ Recent Advances ✘ Summary 2
- 3. CASE : 55yrold male admitted with a diagnosis of SARS-CoV-2 Abdominal distension and bilateral leg swelling for 10 days O/E: T:36.8°C, PR:89 beats/min, RR: 20 breaths/min, BP:147/89 mmHg. Chest: Clear CVS: N/L Bilateral pedal edema(+) Ascites(+) LAB Ix: TC: 9.1x103/μl N: 6.1x103/μl L:1.5x103/μl PT/INR:14.2/1.4 aPTT:36.3 s LDH:768 U/L CRP:49.9 mg/L D-dimer: 8,570 ng/ml Ferritin: 10,599.25 μg/l AST:125 U/L ALP: 210 U/L AFP > 1,660 U/ml. Anti-HCV: Non-reactive Hepatitis B surface antigen: Reactive Baseline chest X-ray showed changes and the patient was categorized as class 3A. Proceeded with high-resolution computed tomography (HRCT) thorax and IL-6 to monitor for progression for severe COVID-19 3
- 4. *A Non-severe CoronavirusDisease 2019 Patient With Persistently High Interleukin-6 Level Nurfarah Lydia Hambali, Malehah Mohd Noh, Shahleni Paramasivam, Tock Hing Chua, Firdaus Hayati, Alvin Oliver Payus, Tze Yuan Tee, Khairul Taufiq Rosli, Mohammad Faruq Abd Rachman Isnadi and Benny O. Manin 4
- 5. Cytokines ✘ Combination oftwo Greek words ✘ CYTO: Cell ✘ KINOS: Movement 5
- 6. Cytokines ✘ Low molecularweight regulatory proteins/ glycoproteins ✘ Secreted by Leukocytes and various other cells in the body in response to a stimuli ✘ Mainly by activated lymphocytes, macrophages and dendritic cells 6 Mediate INFLAMMATORY and IMMUNE reactions
- 7. 7 Cytokine is actuallya general term!!!!! INTERLEUKINS COLONY STIMULATING FACTORS INTERFERON CHEMOKINES LYMPHOKINES MONOKINES
- 8. Properties exhibited bycytokines!!!!! ✘ Pleiotropic ✘ Redundancy ✘ Cascade induction ✘ Synergy ✘ Antagonism 8
- 9. Interleukins ✘ Mediate theleukocyte cross-talk ✘ Upto 38ILs so far identified, named according to the order of discovery ✘ Involved in the pathogenesis of human inflammatory/ autoimmune diseases 9
- 10. Interleukins and othercytokines which have a significant role in acute inflammation are ✘ IL-1 ✘ IL-6 ✘ IL-17 ✘ TNF-α ✘ Chemokines 10
- 11. ✘ Two mostimportant cells which are the sources of most of the cytokines are ✘ MACROPHAGES & T LYMPHOCYTES 11 IL-1 IL-6 TNF-α IL-17 TNF-β
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- 13. ✘ Produced byfibroblasts, monocytes/ macrophages, T-Lymphocytes, B- Lymphocytes, epithelial cells, keratinocytes and various tumor cells ✘ Induced in normal cells by IL-1/ TNF-α / PDGF/ Viral infection *https://www.cusabio.com/c-20945.html 13
- 14. What is IL-6????? ✘Polypeptide of two types of glycoprotein chains ✘ α-Chain lacks-Intracellular region and can only bind to IL-6 with low affinity ✘ Complex compound binds to the high-affinity β-chain and transmits information to the cell through the β-chain 14
- 15. IL-6 contains fourlong alpha-helical chains that are arranged in an up-up- down-down topology 15
- 16. Functions of IL-6 ✘Critical role in regulating the acute phase response, hematopoiesis, inflammation, metabolic control, liver regeneration, bone metabolism and cancer progression. ✘ IL-6 – B cell stimulating factor-2, which induces the production of antibodies by activated B cells ✘ IL-6 binding to TGF-β induces differentiation of primary CD4+ T cells into Th17 cells 16
- 17. The function ofIL-6 in autoimmune and chronic inflammatory diseases 17
- 18. IL6 Family ✘ IL-6 ✘Interleukin-11 (IL-11) ✘ IL-27 p28/IL-30 ✘ Interleukin 31 (IL-31) ✘ Leukaemia inhibitory factor (LIF) ✘ Oncostatin M (OSM) ✘ Ciliary neurotrophic factor (CNTF) ✘ Cardiotrophin-1 (CT-1) ✘ Neuropoietin. 18
- 19. Interleukin-11 ✘ IL-6 –type cytokine ✘ Produced by a variety of stromal cells including fibroblasts, epithelial cells and osteoblasts ✘ Binds to a multimeric receptor complex which contains an IL-11-specific α subunit and a 130 kDa β subunit (gp130) ✘ Stimulates hematopoiesis and hepatocyte production of acute phase response proteins ✘ Inhibits the genesis of adipocytes, activates osteoclasts, alters neural phenotype, stimulates tissue fibrosis and regulates chondrocyte, synoviocyte and B cell function 19
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- 21. IL-27 p28/IL-30 ✘ IL-27p28/IL-30 aka IL-27 ✘ Heterodimeric cytokine consisting of an IL-12 p40-related protein and an IL-12 p35-like protein (p38) ✘ Expressed on activated macrophages and dendritic cells ✘ IL‐27 receptor (IL-27R) expressed and is detected on ○ Naive T cells ○ Natural killer (NK) cells ○ Monocytes ○ Mast cells ○ Vascular endothelium ○ Activated B cells ○ Langerhans' cells 21
- 22. ✘ Signals througha receptor complex consisting of IL‐27α and the protein gp130 ✘ Binding to its receptor is a cause of JAK/STAT pathway activation ✘ Expressed at sites of inflammation in autoimmune/inflammatory diseases, such as ○ RA ○ Systemic sclerosis (SSc) ○ Inflammatory bowel disease (IBD) ○ Multiple sclerosis ○ Sarcoidosis 22
- 23. Interleukin-31 ✘ Anti-parallel four-helixbundle structure ✘ Produced by T helper type 2 cells ✘ Emerging evidence - T cell-derived cytokines are helps in the development of an effective immune response, but when dysregulated they can promote disease ✘ Signals through a receptor complex made of IL-31RA and Oncostatin M receptor β (OSMRβ) expressed in immune and epithelial cells. ✘ These signals activate three pathways: ○ ERK1/2 MAP kinase ○ PI3K/AKT ○ JAK1/2 23
- 24. Leukaemia Inhibitory Factor ✘Is an interleukin 6 class cytokine ✘ Important roles: ○ Inducing differentiation of leukemia cell ○ Inflammatory response ○ Neuronal development ○ Embryonic implantation ○ Stem cell self-renewal ○ Cancer progression ✘ LIF protein is a monomeric glycoprotein which is often modified by glycosylation ✘ The molecular weight of the unglycosylated LIF protein is 20–25 kDa, while the molecular weight of the glycosylated protein is in the range of 37–63 kDa 24
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- 26. Oncostatin M ✘ AkaOSM, is a member of the multifunctional cytokine IL6-type cytokine family ✘ Produced by activated T lymphocytes, macrophages, monocytes, neutrophils and in microglial cells. ✘ OSM is made up of 196 residues. ✘ The genes for OSM and LIF occur in tandem on the human chromosome 22 ✘ Both have very similar gene structures, sharing similar promoter features and intron-exon structure 26
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- 28. Ciliary Neurotrophic Factor ✘Aka CNTF ✘ Signal through intracellular chains of the gp130/LIFRβ receptor ✘ Primary structure of CNTF – Cytosolic protein with strong similarity to the alpha-helical cytokine family - Four anti-parallel helices. ✘ Exerts its activity via complexation with CNTF receptor (CNTF-R). ✘ This complex consists of a CNTF-binding protein (CNTF-R) and two proteins important for signal transduction 28
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- 30. Cardiotrophin-1 ✘ Aka CT-1 ✘201 amino acid member of the IL-6 family of cytokines ✘ Able to induce a hypertrophic response in neonatal cardiac myocytes ✘ Also detected in normal adult human lung ✘ Expressed in both fetal and adult airway smooth muscle cells. ✘ Activates gp130 dependent signaling and stimulates JAK/STAT pathway to transduce hypertrophic and cytoprotective signals in cardiac myocytes. ✘ CT-1 has also a neurotrophic function 30
- 31. Neuropoietin (NP) ✘ Akacardiotrophin-2 ✘ Four-helix bundle structure and signal through gp130-containing receptor complexes. ✘ Promote embryonic motor neuron survival, neural precursor cell proliferation, and astrocyte differentiation in vitro. ✘ NP is expressed when the expression of these other IL-6 family cytokines is low ✘ NP may have a unique role in nervous system development. 31
- 32. IL-6 Signalling Pathway ✘IL-6 Signal - Initiated by binding to its receptor named IL-6R ✘ IL-6R protein has two forms in cells ○ Membrane-bound form ○ Soluble (sIL-6R) form ✘ If cells do not express IL-6R, they can be stimulated by a complex formed by IL-6 and a sIL-6R ✘ Releasing the IL-6R protein presenting cells, which presents a gp130- response to IL-6 cytokines ✘ IL-6 responsive cells are very sensitive to IL -6R. 32
- 33. ✘ IL-6 formsa complex with a specific IL-6R ✘ Bind with two gp130 with high affinity to form a tetramer or hexamer IL-6/IL- 6R/gp130 complex. ✘ Then gp130 conducts biological signaling through two pathways: ○ The JAK/STAT pathway ○ The Ras/MAPK pathway. 33
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- 36. Assay in CentralLab by CHEMILUMINESCENCE 36 SIEMENS ADVIA Centaur XP
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- 39. Il-6 level increasesin autoimmune, chronic inflammatory and autoinflammatory conditions!!!!!!! ✘ COVID-19 ✘ Systemic sclerosis ✘ Inflammatory myopathies ✘ Large vessel vasculitis ✘ Systemic lupus erythematosus ✘ Relapsing polychondritis ✘ Autoimmune hemolytic anemia ✘ Acquired hemophilia A ✘ Cogan’s syndrome ✘ Rheumatoid arthritis ✘ Diabetes( Type 2) ✘ Cancer ✘ Crohn’s disease ✘ Pulmonary arterial hypertension ✘ Atherosclerosis 39
- 40. COVID-19 & IL-6 ✘IL-6 is an important cytokine with pleiotropic functions such as metabolic regulation to inflammation, auto-immunity and acute-phase response ✘ COVID-19 patients – High levels of IL-6 due to pulmonary inflammation and extensive lung damage ✘ COVID-19 infection has an aggressive inflammatory response with a large amount of pro-inflammatory cytokines, known as the ‘cytokine storm’ *Relationship between IL-6 and COVID-19: to be considered during treatment Hafize Seda Vatansever & Eda Becer 40
- 41. Cytokine storm inCOVID-19 ✘ Aggressive inflammatory response - “Cytokine storm.” ✘ Cytokine storm correlated directly with lung injury, multi-organ failure, and unfavorable prognosis of severe COVID-19 ✘ Most important pro-inflammatory cytokines - IL-1, TNF- α, and IL-6. ✘ “Cytokine storm” - Sudden acute increase in circulating IL-6, IL-1, TNF- α, and interferon ✘ Lung injury - Consequence of the cytokine storm that can progress into acute lung injury/ severe form ARDS 41
- 42. ✘ Cytokine storm- Critical life-threating condition ✘ Characterized - Inflammation, Hyperferritinemia, Hemodynamic instability, and multi-organ failure, and if left untreated, it leads to death. ✘ Clinical findings - Action of the proinflammatory cytokines like IL-1, IL-6, IL- 18, IFN-γ, and TNF-α ✘ Pro-inflammatory cytokines and anti-inflammatory cytokines - Elevated in the serum of CS patients. 42
- 43. ✘ Anti-inflammatory therapies ✘Early recognition of CS and the prompt treatment can lead to better outcome. ✘ IL-1 receptor antagonist – Anakinra ✘ Tocilizumab - Recombinant humanized IL-6 receptor antagonist *The COVID-19 Cytokine Storm; What We Know So Far Dina Ragab, Haitham Salah Eldin, Mohamed Taeimah, Rasha Khattab and Ramy Salem 43
- 44. *Tocilizumab among patientswith COVID-19 in the intensive care unit: a multicentre observational study Noa Biran, MD Andrew Ip, MD Jaeil Ahn, PhD Ronaldo C Go, MD Shuqi Wang, MS Shivam Mathura, BA et al. 44
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- 46. *Interleukin-6 Is aBiomarker for the Development of Fatal Severe Acute Respiratory Syndrome Coronavirus 2 Pneumonia André Santa Cruz, Ana Mendes-Frias, Ana Isabel Oliveira, Luís Dias, Ana Rita Matos, Alexandre Carvalho, Carlos Capela et.al 46
- 47. Diabetes mellitus &IL-6 47 *Induces by generation of inflammation by controlling differentiation, migration, proliferation, and cell apoptosis (*2017)
- 48. 48 *Impairment of theinsulin-degrading enzyme (IDE) is associated with obesity and type 2 diabetes mellitus (T2DM)
- 49. Rheumatoid Arthritis &IL-6 49
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- 52. Summary ✘ IL-6 isa pleiotropic cytokine produced by lymphoid and nonlymphoid cells ✘ IL-6 induces a broad range of cellular and physiological responses ✘ IL-6 can be used as a marker to determine the severity of diseases especially in COVID-19 ✘ Low specificity ✘ Researches are going in the filed of IL-6R blocking in view of autoimmune and other inflammatory diseases 52
- 53. References ✘ A Non-severeCoronavirus Disease 2019 Patient With Persistently High Interleukin-6 Level Nurfarah Lydia Hambali, Malehah Mohd Noh et.al ✘ https://www.cusabio.com/c-20945.html ✘ Relationship between IL-6 and COVID-19: to be considered during treatment Hafize Seda Vatansever & Eda Becer ✘ Interleukin-6 Is a Biomarker for the Development of Fatal Severe Acute Respiratory Syndrome Coronavirus 2 Pneumonia André Santa Cruz, Ana Mendes-Frias, Ana Isabel Oliveira, Luís Dias, Ana Rita Matos, Alexandre Carvalho, Carlos Capela et.al ✘ The COVID-19 Cytokine Storm; What We Know So Far Dina Ragab, Haitham Salah Eldin, Mohamed Taeimah, Rasha Khattab and Ramy Salem 53
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