User:Immcarle161/Interleukin 19

Interleukin 19

Interleukin 19 (IL-19) is a protein belongs to IL-10 cytokine subfamily. Human IL-19 is encoded by the IL-19 gene located in the chromosome.

Structure

The IL-19 gene contains 7 exons. Secreted IL-19 protein is made from 159 amino acids in an alpha-helix structure.

Function

IL-19 is an immunosuppressive cytokine that is responsible for both cell type-specific and system-specific down-regulation of inflammation. IL-19 interacts with both immune cells (macrophages, T cells, B cells) and non-immune cells (endothelial cells and brain resident glial cells, etc.).

IL-19 induces immune cells polarization

A demonstration of IL-19 binds to IL20 Receptor on the surface of immune cells to regulate cytokines expression

There are different subpopulations of T cells in the immune system: T helper cells (Th) , cytotoxic T cells (Tc), memory T cells, and regulatory T cells(Treg). T helper cells are further divided based on the different secreted cytokines into Type 1 T helper cells (Th1), Type 2 T helper cells (Th2), T helper type 9 (Th9), T helper 17 cells (Th17), T follicular helper cells (Tfh). Each subgroup expresses different cytokines and maintains different functions. The destiny of T cell subgroups depends on the signals present in their surrounding environment.

IL-19 is homologous to IL-20 and thus is able to bind the interleukin-20 receptor complex. IL-19 binds to dimer receptor IL20R, leading to activation of the JAK/STAT signaling pathway. The activated STAT3 passes through the nuclear envelope of the immune cells to interact with the DNA to regulate cytokines expression. IL-19 increases the production of Th2 cytokines by downregulating interferon gamma ( IFN-γ) and inducingInterleukin Interleukin-4(IL-4) and (IL-10). As a result, IL-19 shifts the Th1 /Th2 balance to favor Th2.

Macrophages can also be polarized and have distinct functional phenotypes after receiving specific signals. When IL-19 binds to the IL-20R receptors on macrophages, it induces expression of IL-10, promoting the macrophage polarization from the M1 type to an anti-inflammatory phenotype M2. The IL-19 induced macrophage polarization reduces the pro-inflammatory cytokines produced by M1 macrophages, thus limiting the magnitude of the inflammatory response.

A demonstration of the protective effect of IL-19 in vascular diseases by decreasing immune cell recruitment to inflamed tissue and reduce oxidative stress.

The protective effect of IL-19 in Vascular Inflammation

Inflammation is present in vascular disease progression. The close interaction between the immune system and the vascular system is due to cytokines and cytokine receptors on different type of cells. Inflammation occurs during the progression of vascular disease, where endothelial cells secrete pro-inflammatory cytokines. As a response to these cytokines, the immune cells are activated and recruited into the major arteries, propagating inflammation and damaging tissue of the arterial wall. Therefore, an anti-inflammatory response to control and downregulate such local inflammatory interaction between immune cells and vascular cells is essential to maintain the heart tissue.

IL-19 is not detectable in healthy arteries, but is found in damaged vessels. IL-19 is secreted by vascular cells to recover from inflammation and protect the vascular tissue. IL-19 down-regulates the inflammation in vascular tissue in several ways:

• IL-19 downregulates the adhesion molecules on the endothelial cells surface to prevent immune cells recruitment during vascular disease
  • IL-19 suppresses the expression of RNA-binding protein HuR, an mRNA stability factor. Without HuR, the adhesion molecule’s mRNA has a shorter half-life and is not stable. Therefore, fewer adhesion molecules are translated and expressed in the endothelial cell lined up in blood vessels. The adhesion molecules are essential for immune cells to exit the blood vessel and enter the inflamed heart tissue. The reduction in adhesion molecule expression prevents immune cells from forming tight binding with the blood vessel, limiting the immune cells' ability to squeeze out through the junctions between vessel epithelial cells. Therefore, with fewer immune cells entering the heart tissue, IL-19 protects the vascular cells from further immune response lead damages.
• IL-19 reduces oxidative stress
  • IL-19 upregulates the expression of heme oxygenase-1 (HO-1) and reduces reactive oxygen species in human vascular smooth muscle cells. The elevation of HO-1 acts as a potent antioxidant that reduces oxidative stress in vascular tissue.
• IL-19 induces immune cells polarization
  • The induction of anti-inflammatory cytokines (IL-10 and IL-4) and downregulating pro-inflammatory cytokines (IFN-γ) pushes a T helper cell away from Th1 to Th2. During vascular infection, Th1 is the predominant T cells population and expresses interferon IFN-γ, IL-12, tumor necrosis factor-α, and other pro-inflammatory cytokines, leading to vessel tissue damage. Th2 is the "opposing force" that balances the Th1 inflammatory cytokines. The Th2 cells secrete IL-4 and IL-10 and downregulate IFN-γ. This dampens the inflammatory response by inhibiting pro-inflammatory gene expression. Additionally, macrophages receiving the IL-19 signal are polarized from M1 (pro-inflammatory) to M2 (anti-inflammatory).

IL-19 Is Neuroprotective

The resident glial cells of the central nervous system participate in neuroinflammation initiation and regulation. Glial cells such as microglia and astrocytes produce inflammatory cytokines in response to foreign antigens and then produce immunosuppressive cytokines to resolve inflammation.  IL-19, secreted by astrocytes, functions as an immunosuppressive signal in a manner of delayed kinetics of induction. The induction of IL-19 often occurs after immune response initiation as a secondary, anti-inflammatory, neuroprotective regulation to limit the inflammation. Astrocytes produce IL-19 to interact with cells expressing IL-20 receptors (microglia etc.), regulating cytokine secretion, such as reducing the production of pro-inflammatory cytokines such as (IL-6 TNF-a). Whether microglia also secret IL-19 in response to neuroinflammation remains contentious.

IL-10 family

Interleukin-19 is a cytokine that belongs to the IL-10 family of cytokines along with several other interleukins including IL-10, IL-20, IL-22, IL-24, IL-26, and several virus-encoded cytokines. It signals through the same cell surface receptor (IL-20R) that is used by IL-20 and IL-24.