Interleukin- 6 (IL-6)
PKGhatak, MD
Interleukins are secreted primarily by immunocytes. Interleukins (ILs) are hormones like chemicals, function as an inflammatory promoters but also act as anti-inflammatory agents. In the biological system, pro and anti, inflammatory agents are neither good nor bad. Both are required to fight infections, autoimmune diseases and cancers and at the same time must be available for repairs of diseased or damaged tissues.
Interleukin 6 (IL-6) is the main Interleukin in the pathogenesis of COID-19 virus inflammatory reactions. In a previous blog, dated July 2020, a general outline of Interleukin was presented. In this article, a more detailed mechanism of action of IL-6 in inflammation is discussed.
Cells capable of secreting IL-6. IL-6 producing cells are Macrophages, endothelial cells of blood vessels, epithelial cells of the gut, and T & B cells (lymphocytes).
Normal serum levels of IL-6 are 0 pmg/ml to 1.8 pmg/ml.(pmg=picomiligram)
How activation of immunocytes occurs.
Bacterial glycoprotein fits the pattern of the Pathogen Associated Molecular Pattern (PAMP) Receptors. Other receptors are Toll Like Receptors (TL) are activated by bacterial lipopolysaccharide [Toll is a german word meaning stunning]. Once these antigens bind with the appropriate receptor IL-6 is produced. Immunocytes can also be activated by cellular metabolic changes, hypoxia, viral infection, activated nuclear factor (NF) k-B (killer B-cells), and NF-IL6 composites.
A general outline of IL-6 effects in the body.
1. IL-6 promotes inflammation. 2. Anti-inflammation. 3. Pathogen clearance. 4. New blood cell formation(hemopoiesis) 5. Reset the metabolic rate of the body. 6. Modification of lipid metabolism. 7. Neural differentiation increased substance-P generation and myelin sheath break-up.
Nature of IL-6.
IL-6 is a small protein molecule containing 212 amino acid residues. IL-6 molecule attaches to its target cells by two pathways. One is by attaching with the universal glycoprotein g130 surface receptors, the other by IL-6R receptors. The IL-6R receptors are present in very limited cell lines – in hepatocytes, macrophages, B-cells and a subset of T-cells.
IL-6 must first bind with IL-6R present on the cell surface, then this composite allows the IL-6 to bind with g130 receptors. As a result, IL-6 R limits IL-6 activities to limited tissues. This is the Classical Path of Activation of immunocytes and the effect on the body is Anti-inflammatory.
Roll of Metalloprotease in Cytokines production.
Activated metalloprotease strips IL-6R from the cell surface membrane. The free IL-6 receptors easily bind with IL-6. Then these composites can easily bind and activate a number of cells in different tissues.
This pathway leads to the unregulated production of cytokines and other mediators. This pathway of immunocyte activation is seen in cancers, autoimmune diseases, arteritis (inflammation of the smooth muscular layer of blood vessels), muscles of the GI tract, heart muscles, brain cells and other tissues. This path of activation of immunocytes is Pro-inflammatory.
IL-6 induced acute inflammation.
IL-6 acts through intermediate cytokines like TNF (tissue necrosis factor), PGE (prostaglandins E) and other interleukins (IL).
Acute phase inflammatory reactants.
Most of the acute phase reactants (APR) are produced and released by hepatocytes. The liver secretes increasing amounts of C-Reactive Protein, hepcidin, and haptoglobin. Fibrinogen, serum amyloid proteins from IL-6 stimulation.
Macrophage.
Macrophages are of 3 types - resident tissue macrophages (RTMs), monocyte-derived macrophages (MDMs), and transitioning MDMs in the tissue.
Macrophages express a number of proinflammatory chemokines and cytokines, including IL-1β, IL-6, IL-8, CXCL10, and TNFα. And a macrophage subset termed Macro_c2-CCL3L1, which specifically expressed CCL8, CXCL10/11, and IL-6, and a monocyte subset termed Mono_c1-CD14-CCL3, which abundantly expressed IL-1β, CCL20, CXCL2, CXCL3, CCL3, CCL4, and TNF alpha.
Macrophage hyperactivation.
Hyperstimulated macrophages produce Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome. Hemophagocytosis (i.e., engulfment of erythrocytes by activated macrophages), systemic inflammation, fever, cytopenia, hyperferritinemia, and hyperlipidemia, which can be due to inherited defects in cytotoxic T-cell function or triggered secondary to infection or rheumatological disorders.
This hyperactive IL-6 is seen often in covid related bilateral interstitial pneumonia and multisystem failure and deaths.
IL-6 plays an important function in both innate and acquired immunity - first to limit infection, and invasion of harmful pathogens, toxins, venom, and cancers. Then in the second phase, it helps to heal the tissue by removing debris and dead pathogens, followed by the formation of collagen fibers, new cells and new blood vessel growth. In the initial stage of infection, treatment should promote inflammation and not limit it. In macrophage induced hyperactive stage, intervention should be directed to stop cytokines or neutralize cytokines in limiting tissue damage. If interventions are not properly timed then such interventions do more harm than good. For example, at the beginning of covid infection and symptoms, if drugs are used to kill the virus, or antibody infusion to neutralize the virus then these interventions are beneficial. Medications and biological agents that limit acute inflammatory reactions are detrimental when used in this phase of infection.
In any discussion of covid, specially in newspapers and social media, there is hardly any attention paid to what and when such interventions were done. Such discussions are useless and harmful.
Role of IL-6 in a few select organs.
Brain.
IL-6 crosses the blood-brain barrier. IL-6 induces PGE2 (prostaglandin E2) in the Hypothalamus. (Hypothalamus acts as the Thermostat of the body temperature). In response, the skeletal muscles generate body heat by non-shivering thermogenesis, catabolism of fatty acids and depletion of body fat. It also improves glucose utilization by increasing GLP 1(glucagon like peptide) and Amylin secretion from the pancreas.
Lungs.
In normal circumstances, IL-6 helps to maintain the integrity of lung elastic tissues, alveolar membrane, maintain pulmonary BP and preserve pulmonary microcirculation. In overactive IL-6, the proinflammatory effects override the anti-inflammatory functions and produce the following changes -
IL-6 induced cytokines damage pneumocytes II and damages endothelial cells of the pulmonary capillaries. It produces alveolar and interstitial edema and micro atelectasis. Pulmonary hypertension develops due to platelet microemboli. Gas exchanges are hampered and hypoxia develops.
Liver.
Increased production of the acute phase reactants is already mentioned. The liver also reduces the production and release of Fibronectin and Transferrin into circulation.
GI tract.
Increased hepcidin blocks the action of Ferroproteins (normally carry iron from the gut to bone marrow for RBC production) leading to anemia of infection.
On other viruses.
Enterovirus 71. It causes Hand- Foot - Mouth disease in humans. Under IL6 stimulation enterovirus 71 invades the brain and produces encephalitis.
Herpes virus increases its virulence and produces Kaposi sarcoma.
IL6 is implicated in the following diseases.
Diabetes mellitus, Alzheimer's disease. Amyloidosis, Rheumatoid arthritis, Lupus erythematosus, Multiple myeloma, Bechet disease, Multiple sclerosis, Neuromyelitis Optica, Prostatic cancer.
Interleukin 6 is an important Cytokine and possesses a multitude of functional potentials. The covid pandemic has brought IL-6 cytokine to the general public domain. Covid discussions are commonplace in social media and everyone has an opinion with or without the basic knowledge of Interleukins, specially IL-6.
Covid vaccine is as sure a preventive measure as one can possibly create but the vaccines are kept in warehouses while unvaccinated people are engaged in endless debate over the use of antiviral drugs and biological immunosuppressive and Immunopotentiation therapies.
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