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Interleukin 19 (IL-19) is an immunosuppressive
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that belongs to the IL-10 cytokine subfamily. Human IL-19 is encoded by the IL-19
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
which codes for 9 exons and is located on
chromosome A chromosome is a package of DNA containing part or all of the genetic material of an organism. In most chromosomes, the very long thin DNA fibers are coated with nucleosome-forming packaging proteins; in eukaryotic cells, the most import ...
1. The IL-19 protein is composed of 159 amino acids and has a quaternary structure with alpha helix motifs and loops. IL-19 is preferentially expressed in monocytes, macrophages, and T and B lymphocytes, but interacts with immune cells (
macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s,
T cell T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell ...
s,
B cell B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...
s) and non-immune cells (
endothelial cells The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the res ...
and brain resident
glia Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (the brain and the spinal cord) and in the peripheral nervous system that do not produce electrical impulses. The neuroglia make up ...
l cells, etc). IL-19 initiates
JAK-STAT The JAK-STAT signaling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death, and tumor formation. The pathway communicates information from chemical signals outs ...
signaling which activates genes and creates mRNA sequences (
transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, often th ...
) that are translated into proteins (
translation Translation is the communication of the semantics, meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The English la ...
) which have downstream effector functions. IL-19 signaling uses IL-20 dimer receptor complexes that bind the IL-19 ligand,
Janus kinase Janus kinase (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 and 2 (since they were just two of many discoverie ...
s (JAKs), and the signal transducer and activator of transcription 3 (
STAT3 Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the ''STAT3'' gene. It is a member of the STAT protein family. Function STAT3 is a member of the STAT protein family. In respon ...
) to initiate the molecular signaling cascade shown on the diagram on the right.


Function

IL-19 is associated with broad functions across inflammation, cell development, viral responses, and lipid metabolism. As an immunosuppressive cytokine, IL-19 promotes the Th2 (regulatory) T-cell response which supports an anti-inflammatory lymphocyte phenotype, dampens the Th1 T-cell response and inflammatory cytokine secretion (
IFNγ Interferon gamma (IFNG or IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. ...
), increases IL-10 (anti-inflammatory) expression in peripheral blood mononuclear cells (
PBMC A peripheral blood mononuclear cell (PBMC) is any peripheral blood cell having a round nucleus. These cells consist of lymphocytes (T cells, B cells, NK cells) and monocytes, whereas erythrocytes and platelets have no nuclei, and granulocytes (ne ...
), and inhibits the production of
immunoglobulin G Immunoglobulin G (IgG) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG ...
(IgG) from
B cell B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...
s.


Cell adhesion molecule regulation

IL-19 suppresses the expression of RNA-binding protein HuR. This protein is responsible for stabilizing mRNA that codes for
cell adhesion molecule Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help cells stick to each ...
s (CAMs) which are secreted by activated macrophages and facilitate
neutrophil Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in differe ...
extravasation into peripheral or
cardiac The heart is a muscular organ found in humans and other animals. This organ pumps blood through the blood vessels. The heart and blood vessels together make the circulatory system. The pumped blood carries oxygen and nutrients to the tissu ...
tissue. The downregulation of this factor affects the translation adhesion molecules which are expressed in the endothelial cells lined up in blood vessels. A reduced number of neutrophils entering cardiac tissue serves as a protective mechanism that limits the vascular tissue damage that ensues from inflammatory processes.


Chronic inflammatory disease

IL-19 has been reported to enhance chronic inflammatory diseases. IL-19 is produced by and regulates cells of the monocyte lineage, such as alveolar
macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s and lung
dendritic cell A dendritic cell (DC) is an antigen-presenting cell (also known as an ''accessory cell'') of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system ...
s. Several studies have used IL-19-deficient (IL-19-/-) mice and tested them at baseline (naïve) and following immune challenge with microbial products or recombinant cytokines. Naïve IL-19-/- mice show a decreased percentage of monocyte-derived cells and express significantly less MHC class II in response to stimulation with exogenous antigens such as
lipopolysaccharide Lipopolysaccharide (LPS), now more commonly known as endotoxin, is a collective term for components of the outermost membrane of the cell envelope of gram-negative bacteria, such as '' E. coli'' and ''Salmonella'' with a common structural archit ...
(LPS). IL-19-/- mice also show dysregulated neurogenic-locus-notch-homolog-protein-2 (
Notch2 Neurogenic locus notch homolog protein 2 (Notch 2) is a protein that in humans is encoded by the ''NOTCH2'' gene. NOTCH2 is associated with Alagille syndrome and Hajdu–Cheney syndrome. Function Notch 2 is a member of the notch family. Me ...
) expression which plays a role in cell differentiation. Since
MHC class II MHC Class II molecules are a class of major histocompatibility complex (MHC) molecules normally found only on professional antigen-presenting cells such as dendritic cells, macrophages, some endothelial cells, thymic epithelial cells, and B cell ...
mediates peptide presentation to T cells and Notch 2 determines cell fate decision, endogenous IL-19 appears to regulate both processes.


Immune cell polarization

The induction of the anti-inflammatory cytokines IL-10 and IL-4 and the downregulation of pro-inflammatory cytokines such as
IFN-γ Interferon gamma (IFNG or IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. ...
shifts the phenotype of a
T helper cell The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...
away from T-helper 1 (Th1) phenotype and towards the T-helper 2 (Th2) phenotype. This process of immune cell polarization occurs when immune cells adopt distinct programs and perform specialized functions in response to specific signals. During vascular infection (bacterial, fungal or viral infection develops within an artery or a vein), the Th1 phenotype predominates in the T cell population, and interferon-gamma (
IFN-γ Interferon gamma (IFNG or IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. ...
), tumor necrosis factor-alpha (
TNF-α Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...
), and other pro-inflammatory cytokines are secreted at high levels. If cytokine secretion is left unrestricted, there may be potential consequences including vessel or tissue damage. In contrast, cells with the Th2 phenotype secrete IL-4 and IL-10 and downregulate IFN-γ which collectively dampen the inflammatory response. Analogously to
lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), an ...
s,
macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s receiving the IL-19 signal are polarized from the pro-inflammatory phenotype ( M1) to the anti-inflammatory phenotype ( M2).


Neutrophil development

Osteocyte An osteocyte, an oblate-shaped type of bone cell with dendritic processes, is the most commonly found cell in mature bone. It can live as long as the organism itself. The adult human body has about 42 billion of them. Osteocytes do not divide an ...
s are the most abundant cells in the bone and they are responsible for bone health. Osteocytes are important regulators of hematopoiesis so they are important in aiding cellular development. Studies with mice have shown that the constitutive activation of mechanistic target of rapamycin complex (a
protein complex A protein complex or multiprotein complex is a group of two or more associated polypeptide chains. Protein complexes are distinct from multidomain enzymes, in which multiple active site, catalytic domains are found in a single polypeptide chain. ...
that functions as a nutrient/energy /redox sensor and controls protein synthesis), or
mTORC1 mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis. mTOR Complex 1 (mTORC1) is comp ...
in osteocytes shows a dramatic increase in IL-19 production and expands neutrophil precursor numbers. IL-19 administration also stimulated neutrophil development but the depletion of endogenous IL-19 or its cognate receptor inhibited cell development, suggesting that IL-19 is an essential regulator of neutrophil development.


Lipid metabolism

Nonalcoholic steatohepatitis (NASH) is a disease that has progressed from nonalcoholic fatty liver disease (NAFLD) and is characterized by inflammation and
fibrosis Fibrosis, also known as fibrotic scarring, is the development of fibrous connective tissue in response to an injury. Fibrosis can be a normal connective tissue deposition or excessive tissue deposition caused by a disease. Repeated injuries, ch ...
. Findings showed that the effects of a high fat diet on liver injury, inflammation, and fibrosis were significantly worse in IL-19 gene-deficient mice than controls. This is congruous with a significantly higher secretion of IL-6, TNF-α, and TGF-β secretion (pro-inflammatory cytokines) in IL-19 gene-deficient mice. IL-19 administration decreased triglyceride and cholesterol levels in
HepG2 Hep G2 (or HepG2) is a human liver cancer cell line. Hep G2 is an immortal cell line which was derived in 1975 from the liver tissue of a 15-year-old Caucasian male from Argentina with a well-differentiated hepatocellular carcinoma. ...
cells (isolated from a hepatocellular carcinoma patient) and the expression of fatty acid synthesis-related enzymes (reduced
lipogenesis In biochemistry, lipogenesis is the conversion of fatty acids and glycerol into Adipose tissue, fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in adipose, fat. Lipogenesis encompasses both fatty aci ...
). IL-19 is therefore closely linked to the suppression of lipid metabolism.


Neuroprotection

The resident glial cells of the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
participate in the initiation and regulation of neuroinflammation. Glial cells such as
microglia Microglia are a type of glia, glial cell located throughout the brain and spinal cord of the central nervous system (CNS). Microglia account for about around 5–10% of cells found within the brain. As the resident macrophage cells, they act as t ...
and
astrocyte Astrocytes (from Ancient Greek , , "star" and , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of en ...
s secrete proinflammatory cytokines in response to foreign antigens and immunosuppressive cytokines to resolve
inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
at the recovery phase of the immune response. Within the brain, IL-19 is secreted by astrocytes in a delayed fashion. The IL-19 ligand interacts with cells expressing IL-20 receptors such as microglia and initiate a signaling cascade that regulates
cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
secretion. IL-19 signaling acts as secondary neuroprotective pathway that limits the inflammatory response and protect the brain from CNS insults.


Autoimmunity

IL-17A is implicated in the immune response and in the pathogenesis of inflammatory autoimmune diseases such as
psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by patches of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small localized patches to complete b ...
. IL-17A upregulates IL-19, IL-20, and IL-24 and this was shown by enhanced IL-17A expression using anti-IL-10
neutralizing antibodies A neutralizing antibody (NAb) is an antibody that defends a cell from a pathogen or infectious particle by neutralizing any effect it has biologically. Neutralization renders the particle no longer infectious or pathogenic. Neutralizing antibo ...
(block IL-10 inhibitory effects and facilitate cytokine secretion). Findings showed upregulated IL-23/IL-17 pathway related cytokines, IL-19, and IL-24, pronounced inflammation, and
keratinocyte Keratinocytes are the primary type of cell found in the epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells. Basal cells in the basal layer (''stratum basale'') of the skin are sometimes referre ...
proliferation.


HIV

The most effective current treatment for HIV is combination antiretroviral therapy (cART) which stops the virus from making copies of itself using host cells and slows down the development of AIDS. Although cART therapy can help HIV-infected patients recover CD4+ T cells, there are several factors that affect T cell restoration and the maintenance of an undetectable viral load. One of these factors is
single nucleotide polymorphisms In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...
(SNPs) in immune relevant cytokines (IL-15, IFNγ, IL-19). While many individuals respond to cART, there are individuals who are immunological non-responders (INR) which means that the density of T helper cells they have is below the 200 cells/μL threshold after two years on successful cART. Correlational studies have shown that polymorphisms in the IFNγ and IL-19 genes significantly impact the probability of failing to achieve an optimal immune recovery in HIV-patients starting cART.


Other relevant functions

IL-19 upregulates the expression of heme oxygenase-1 (HO-1) and reduces
reactive oxygen species In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...
in human vascular
smooth muscle Smooth muscle is one of the three major types of vertebrate muscle tissue, the others being skeletal and cardiac muscle. It can also be found in invertebrates and is controlled by the autonomic nervous system. It is non- striated, so-called bec ...
cells.


IL-10 family

Interleukin-19 is a
cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
that belongs to the IL-10 family of cytokines along with several other
interleukin Interleukins (ILs) are a group of cytokines (secreted proteins and signal molecules) that are expressed and secreted by white blood cells (leukocytes) as well as some other body cells. The human genome encodes more than 50 interleukins and related ...
s including IL-10, IL-20, IL-22, IL-24, IL-26, and several
virus A virus is a submicroscopic infectious agent that replicates only inside the living Cell (biology), cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Viruses are ...
-encoded cytokines. It signals through the same cell surface receptor (IL-20R) that is used by IL-20 and IL-24.


References


External links

* {{NLM content Interleukins