Interleukin 6
Encyclopedia
Interleukin-6 is a protein
that in humans is encoded by the IL6 gene
.
IL-6 is an interleukin
that acts as both a pro-inflammatory and anti-inflammatory cytokine
. It is secreted by T cell
s and macrophage
s to stimulate immune response, e.g. during infection and after trauma, especially burns or other tissue damage leading to inflammation. In terms of host response to a foreign pathogen during infection, IL-6 has been shown, in mice, to be required for resistance against the bacterium, Streptococcus pneumoniae
. IL-6 is also a "myokine," a cytokine produced from muscle, and is elevated in response to muscle contraction. It is significantly elevated with exercise, and precedes the appearance of other cytokines in the circulation. During exercise, it is thought to act in a hormone-like manner to mobilize extracellular substrates and/or augment substrate delivery. Additionally, osteoblast
s secrete IL-6 to stimulate osteoclast
formation. Smooth muscle cells in the tunica media
of many blood vessels also produce IL-6 as a pro-inflammatory cytokine
. IL-6's role as an anti-inflammatory cytokine is mediated through its inhibitory effects on TNF-alpha and IL-1
, and activation of IL-1ra
and IL-10
.
and of the acute phase response. It is capable of crossing the blood brain barrier and initiating synthesis of PGE2 in the hypothalamus
, thereby changing the body's temperature setpoint. In muscle and fatty tissue, IL-6 stimulates energy mobilization which leads to increased body temperature. IL-6 can be secreted by macrophages in response to specific microbial molecules, referred to as pathogen
associated molecular patterns (PAMPs). These PAMPs bind to highly important group of detection molecules of the innate immune system
, called pattern recognition receptors (PRRs
), including Toll-like receptors (TLR
s). These are present on the cell surface and intracellular compartments and induce intracellular signaling cascades that give rise to inflammatory cytokine production.
IL-6 is also essential for hybridoma
growth and is found in many supplemental cloning media such as briclone. Inhibitors of IL-6 (including estrogen
) are used to treat postmenopausal osteoporosis
. IL-6 is also produced by adipocytes and is thought to be a reason why obese individuals have higher endogeneous levels of CRP
. In a 2009 study, intranasally administered IL-6 was shown to improve sleep-associated consolidation
of emotional memories.
IL-6 is responsible for stimulating acute phase protein synthesis, as well as the production of neutrophils in the bone marrow. It supports the growth of B cells and is antagonistic to regulatory T cells.
complex consisting of the ligand-binding IL-6Rα chain (CD126
), and the signal-transducing component gp130 (also called CD130). CD130 is the common signal transducer for several cytokines including leukemia inhibitory factor
(LIF), ciliary neurotropic factor, oncostatin M
, IL-11
and cardiotrophin-1, and is almost ubiquitously expressed in most tissues. In contrast, the expression of CD126 is restricted to certain tissues. As IL-6 interacts with its receptor, it triggers the gp130 and IL-6R proteins to form a complex, thus activating the receptor. These complexes bring together the intracellular
regions of gp130 to initiate a signal transduction cascade through certain transcription factors, Janus kinases (JAK
s) and Signal Transducers and Activators of Transcription (STAT
s).
IL-6 is probably the best studied of the cytokines that use gp130, also known as IL-6 signal transducer (IL6ST), in their signalling complexes. Other cytokines that signal through receptors containing gp130 are Interleukin 11
(IL-11), Interleukin 27
(IL-27), ciliary neurotrophic factor
(CNTF), cardiotrophin-1 (CT-1), cardiotrophin-like cytokine
(CLC), leukemia inhibitory factor
(LIF), oncostatin M
(OSM), Kaposi's sarcoma-associated herpesvirus
interleukin 6 like protein (KSHV-IL6). These cytokines are commonly referred to as the IL-6 like or gp130 utilising cytokines
In addition to the membrane-bound receptor, a soluble form of IL-6R (sIL-6R) has been purified from human serum and urine. Many neuronal cells are unresponsive to stimulation by IL-6 alone, but differentiation and survival of neuronal cells can be mediated through the action of sIL-6R. The sIL-6R/IL-6 complex can stimulate neurites outgrowth promote survival of neurons, hence may be important in nerve regeneration through remyelination.
with interleukin-6 receptor
. and glycoprotein 130
.
, depression, Alzheimer's Disease
, systemic lupus erythematosus
, prostate cancer
, and rheumatoid arthritis
.
Advanced/metastatic cancer patients have higher levels of IL-6 in their blood.
Hence there is an interest in developing anti-IL-6
agents as therapy against many of these diseases. The first such is tocilizumab
which has been approved for rheumatoid arthritis
. Another, ALD518
, is in clinical trials.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the IL6 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
IL-6 is an interleukin
Interleukin
Interleukins are a group of cytokines that were first seen to be expressed by white blood cells . The term interleukin derives from "as a means of communication", and "deriving from the fact that many of these proteins are produced by leukocytes and act on leukocytes"...
that acts as both a pro-inflammatory and anti-inflammatory cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
. It is secreted by T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
s and macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s to stimulate immune response, e.g. during infection and after trauma, especially burns or other tissue damage leading to inflammation. In terms of host response to a foreign pathogen during infection, IL-6 has been shown, in mice, to be required for resistance against the bacterium, Streptococcus pneumoniae
Streptococcus pneumoniae
Streptococcus pneumoniae, or pneumococcus, is Gram-positive, alpha-hemolytic, aerotolerant anaerobic member of the genus Streptococcus. A significant human pathogenic bacterium, S...
. IL-6 is also a "myokine," a cytokine produced from muscle, and is elevated in response to muscle contraction. It is significantly elevated with exercise, and precedes the appearance of other cytokines in the circulation. During exercise, it is thought to act in a hormone-like manner to mobilize extracellular substrates and/or augment substrate delivery. Additionally, osteoblast
Osteoblast
Osteoblasts are mononucleate cells that are responsible for bone formation; in essence, osteoblasts are specialized fibroblasts that in addition to fibroblastic products, express bone sialoprotein and osteocalcin.Osteoblasts produce a matrix of osteoid, which is composed mainly of Type I collagen...
s secrete IL-6 to stimulate osteoclast
Osteoclast
An osteoclast is a type of bone cell that removes bone tissue by removing its mineralized matrix and breaking up the organic bone . This process is known as bone resorption. Osteoclasts were discovered by Kolliker in 1873...
formation. Smooth muscle cells in the tunica media
Tunica media
The tunica media is the middle layer of an artery or vein.-Artery:It is made up of smooth muscle cells and elastic tissue...
of many blood vessels also produce IL-6 as a pro-inflammatory cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
. IL-6's role as an anti-inflammatory cytokine is mediated through its inhibitory effects on TNF-alpha and IL-1
IL1A
Interleukin-1 alpha is a protein that in humans is encoded by the IL1A gene.The protein encoded by this gene is a cytokine of the interleukin-1 family. Interleukin-1 alpha possesses a wide spectrum of metabolic, physiological, haematopoietic activities, and plays one of the central roles in the...
, and activation of IL-1ra
Interleukin 1 receptor antagonist
The interleukin-1 receptor antagonist is a protein that in humans is encoded by the IL1RN gene.IL-1RA was initially called the IL-1 inhibitor and was discovered separately in 1984 by two independent laboratories. IL-1RA, is an agent that binds non-productively to the cell surface interleukin-1...
and IL-10
Interleukin 10
Interleukin-10 , also known as human cytokine synthesis inhibitory factor , is an anti-inflammatory cytokine. In humans IL-10 is encoded by the IL10 gene....
.
Function
IL-6 is one of the most important mediators of feverFever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
and of the acute phase response. It is capable of crossing the blood brain barrier and initiating synthesis of PGE2 in the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
, thereby changing the body's temperature setpoint. In muscle and fatty tissue, IL-6 stimulates energy mobilization which leads to increased body temperature. IL-6 can be secreted by macrophages in response to specific microbial molecules, referred to as pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
associated molecular patterns (PAMPs). These PAMPs bind to highly important group of detection molecules of the innate immune system
Innate immune system
The innate immune system, also known as non-specific immune system and secondary line of defence, comprises the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner...
, called pattern recognition receptors (PRRs
PRRS
PRRS can refer to:*Porcine Reproductive and Respiratory Syndrome Virus*Radical Socialist Republican Party...
), including Toll-like receptors (TLR
Toll-like receptor
Toll-like receptors are a class of proteins that play a key role in the innate immune system. They are single, membrane-spanning, non-catalytic receptors that recognize structurally conserved molecules derived from microbes...
s). These are present on the cell surface and intracellular compartments and induce intracellular signaling cascades that give rise to inflammatory cytokine production.
IL-6 is also essential for hybridoma
Hybridoma
Hybridoma technology is a technology of forming hybrid cell lines by fusing a specific antibody-producing B cell with a myeloma cell that is selected for its ability to grow in tissue culture and for an absence of antibody chain synthesis...
growth and is found in many supplemental cloning media such as briclone. Inhibitors of IL-6 (including estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
) are used to treat postmenopausal osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
. IL-6 is also produced by adipocytes and is thought to be a reason why obese individuals have higher endogeneous levels of CRP
C-reactive protein
C-reactive protein is a protein found in the blood, the levels of which rise in response to inflammation...
. In a 2009 study, intranasally administered IL-6 was shown to improve sleep-associated consolidation
Memory consolidation
Memory consolidation is a category of processes that stabilize a memory trace after the initial acquisition. Consolidation is distinguished into two specific processes, synaptic consolidation, which occurs within the first few hours after learning, and system consolidation, where...
of emotional memories.
IL-6 is responsible for stimulating acute phase protein synthesis, as well as the production of neutrophils in the bone marrow. It supports the growth of B cells and is antagonistic to regulatory T cells.
Receptor
IL-6 signals through a cell-surface type I cytokine receptorType I cytokine receptor
Type I cytokine receptors are transmembrane receptors expressed on the surface of cells that recognize and respond to cytokines with four α-helical strands. These receptors are also known under the name hemopoietin receptors, and share a common amino acid motif in the extracellular portion...
complex consisting of the ligand-binding IL-6Rα chain (CD126
Cluster of differentiation
The cluster of differentiation is a protocol used for the identification and investigation of cell surface molecules present on white blood cells, providing targets for immunophenotyping of cells...
), and the signal-transducing component gp130 (also called CD130). CD130 is the common signal transducer for several cytokines including leukemia inhibitory factor
Leukemia inhibitory factor
Leukemia inhibitory factor, or LIF, an interleukin 6 class cytokine, is a protein in cells that affects cell growth and development.-Function:LIF derives its name from its ability to induce the terminal differentiation of myeloid leukemic cells...
(LIF), ciliary neurotropic factor, oncostatin M
Oncostatin M
Oncostatin M, also known as OSM, is a protein that in humans is encoded by the OSM gene.OSM is a pleiotropic cytokine that belongs to the interleukin 6 group of cytokines. Of these cytokines it most closely resembles leukemia inhibitory factor in both structure and function...
, IL-11
Interleukin 11
Interleukin 11 is a protein that in humans is encoded by the IL11 gene.IL-11 is a multifunctional cytokine first isolated in 1990 from bone marrow-derived stromal cells. It is a key regulator of multiple events in hematopoiesis, most notably the stimulation of megakaryocyte maturation...
and cardiotrophin-1, and is almost ubiquitously expressed in most tissues. In contrast, the expression of CD126 is restricted to certain tissues. As IL-6 interacts with its receptor, it triggers the gp130 and IL-6R proteins to form a complex, thus activating the receptor. These complexes bring together the intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
regions of gp130 to initiate a signal transduction cascade through certain transcription factors, Janus kinases (JAK
Jak
Jak may refer to:*JAK, Jazakomu Allahu Khayran *JAK members bank, a Swedish interest-free bank*Janus kinase, an intracellular signaling molecule; component of the JAK-STAT signal system...
s) and Signal Transducers and Activators of Transcription (STAT
STAT
STAT may mean:*STAT protein, the Signal Transducers and Activators of Transcription protein*Special Tertiary Admissions Test, a set of tests aimed at assessing the critical reasoning abilities of university applicants who lack other formal qualifications...
s).
IL-6 is probably the best studied of the cytokines that use gp130, also known as IL-6 signal transducer (IL6ST), in their signalling complexes. Other cytokines that signal through receptors containing gp130 are Interleukin 11
Interleukin 11
Interleukin 11 is a protein that in humans is encoded by the IL11 gene.IL-11 is a multifunctional cytokine first isolated in 1990 from bone marrow-derived stromal cells. It is a key regulator of multiple events in hematopoiesis, most notably the stimulation of megakaryocyte maturation...
(IL-11), Interleukin 27
Interleukin 27
Interleukin-27 is a heterodimeric cytokine belonging to the IL-12 family that is composed of two subunits, Epstein-Barr virus -induced gene 3 and IL27-p28 ....
(IL-27), ciliary neurotrophic factor
Ciliary neurotrophic factor
Ciliary neurotrophic factor is a protein that in humans is encoded by the CNTF gene.CNTF has also been shown to be expressed by cells on the bone surface, and to reduce the activity of bone forming cells, osteoblasts.- Satiety effects :...
(CNTF), cardiotrophin-1 (CT-1), cardiotrophin-like cytokine
CLCF1
Cardiotrophin-like cytokine factor 1 , also known as Novel Neurotrophin-1 or B cell-stimulating factor-3 , is a protein that in humans is encoded by the CLCF1 gene.- Function :...
(CLC), leukemia inhibitory factor
Leukemia inhibitory factor
Leukemia inhibitory factor, or LIF, an interleukin 6 class cytokine, is a protein in cells that affects cell growth and development.-Function:LIF derives its name from its ability to induce the terminal differentiation of myeloid leukemic cells...
(LIF), oncostatin M
Oncostatin M
Oncostatin M, also known as OSM, is a protein that in humans is encoded by the OSM gene.OSM is a pleiotropic cytokine that belongs to the interleukin 6 group of cytokines. Of these cytokines it most closely resembles leukemia inhibitory factor in both structure and function...
(OSM), Kaposi's sarcoma-associated herpesvirus
Kaposi's sarcoma-associated herpesvirus
Kaposi's sarcoma-associated herpesvirus is one of seven currently known human cancer viruses, or oncoviruses. It is also the eighth human herpesvirus; its formal name according to the International Committee on Taxonomy of Viruses is HHV-8. Like other herpesviruses, its informal name is used...
interleukin 6 like protein (KSHV-IL6). These cytokines are commonly referred to as the IL-6 like or gp130 utilising cytokines
In addition to the membrane-bound receptor, a soluble form of IL-6R (sIL-6R) has been purified from human serum and urine. Many neuronal cells are unresponsive to stimulation by IL-6 alone, but differentiation and survival of neuronal cells can be mediated through the action of sIL-6R. The sIL-6R/IL-6 complex can stimulate neurites outgrowth promote survival of neurons, hence may be important in nerve regeneration through remyelination.
Interactions
Interleukin 6 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with interleukin-6 receptor
Interleukin-6 receptor
Interleukin 6 receptor also known as CD126 is a type I cytokine receptor....
. and glycoprotein 130
Glycoprotein 130
Glycoprotein 130 is a transmembrane protein which is the founding member of the class of all cytokine receptors. It forms one subunit of type I cytokine receptors within the IL-6 receptor family...
.
Role in disease
IL-6 is relevant to many diseases such as diabetes, atherosclerosisAtherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
, depression, Alzheimer's Disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
, systemic lupus erythematosus
Systemic lupus erythematosus
Systemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...
, prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
, and rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
.
Advanced/metastatic cancer patients have higher levels of IL-6 in their blood.
Hence there is an interest in developing anti-IL-6
Anti-IL-6
Anti-interleukin-6 agents are a recent class of therapeutics.Interleukin-6 is relevant to many inflammatory diseases and many cancers. Hence anti-IL-6 agents have been sought....
agents as therapy against many of these diseases. The first such is tocilizumab
Tocilizumab
Tocilizumab is an immunosuppressive drug, mainly for the treatment of rheumatoid arthritis and systemic juvenile idiopathic arthritis, a severe form of RA in children. It is a humanized monoclonal antibody against the interleukin-6 receptor...
which has been approved for rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
. Another, ALD518
ALD518
BMS-945429 is an aglycosylated, humanized monoclonal antibody against interleukin-6. It is an investigational drug for cancer and rheumatoid arthritis due to its anti-inflammatory properties....
, is in clinical trials.