Structural Biochemistry/IL23R

IL23R gene (interleukin 23 receptor) is one of the members of IL gene family. The genes in the IL family give instruction for making interleukins and interleukin receptors. Interleukins are the subset of cytokines, small proteins which participate in the communication between cells. They are involved in immunity, inflammation, and hematopoiesis.

Location of IL23R: http://ghr.nlm.nih.gov/dynamicImages/chromomap/IL23R.jpeg

Function of IL23R
IL23R provides instructions for the production of the protein “interleukin 23 receptor” (IL-23 receptor). This protein is composed of interleukin 12 receptor-beta-1 chain (IL-12RB1) and interleukin 23 alpha subunit p19 ( IL23A ). It anchors in the cell membrane of T cells, natural killer cells, monocytes, and dendritic cells.

Interleukin 23 receptor interacts with a cytokine, interleukin 23, which produces a complex somewhat like a lock-key model. When there is an interaction between IL-23 and its receptor, chemical signals are triggered which regulate inflammation and the immune systems response to extracellular bacteria.

When IL-23 receptor is stimulated, it would lead to gene transcription of genes which encodes the anti-apoptotic proteins and pro-inflammatory cytokines through the activation of STAT nuclear kappa factors.

Pathway of the signaling of IL23
Below is the pathway of the IL23 signaling, which is important in maintaining a population of Th17 cells, a recently discovered T-cell subset. Th17 cells are mainly involved in antimicrobial immunity and are create inflammation and tissue damage in many autoimmune diseases.

1) When interleukin 23 binds to its receptor, there will be conformation change in the cytoplasmic tails of the receptor.

2) The component of IL-23 receptor, interleukin 23 alpha subunit p19, associates with Janus kinase (Jak2) which is protein implicated in signaling by type II cytokine receptor family, a signal transducer and the activator of transcription STAT3. Another component of IL-23 receptor, interleukin 12 receptor-beta-1 chain (IL-12RB1), interacts with tyrosine kinase 2 (Tyk2). The activation of STAT3 induced by IL-23 makes Interleukin-17 (IL-17) and Interleukin 17F promoters to bind to phosphorylated STAT3.

3) STAT3 regulates the expression of a Th17 transcriptional regulator, Retinoic Acid Receptor-Related Orphan Receptor Gamma-T (ROR-gamma). It is important as it is involved the expression of IL-17 and IL-17F.

4)JAK2 activation induced by IL-23 triggers different pathways, including phosphoinositide-3-kinase (PI3K)/RAC-alpha serine/threonine kinase (AKT) and Nuclear factor kappa B (NGkB). These pathways are necessary for the production of IL-17 production.

5) The IL17 promoter binds to V-rel reticuloendotheliosis viral oncogene homolog A, nuclear factor of kappa light polypeptide gene enhancer in B- cells 1 (p105) (NF-kB1 (p50) and in B-cells 3 (p65) (RelA (p65 NF-kB subunit) . This binding regulates the IL17 expression

6) Suppressor of cytokine signaling 3 (SOCS3) inhibits the activity of JAK2. It thus decreases the IL17 and IL17F expression induced by IL23.

Th17
The pathway above is important in regulating Th17 population. Th17 contributes much to inflammatory disease and they are very in mucosal defense. They differenciate in the presence of nuclear hormone receptor RORγt and other transcription factors. They produce cytokines which stimulate the production of antimicrobial proteins at epithelial cells and hence defending against microbe.

Illness associated with IL23R gene
1. Crohn disease

It can be caused by several variations in or near IL23R gene. It is a chronic disorder which affects the digestive system. Symptoms include diarrhea, rectal bleeding, abdominal cramps, and the need of mobbing bowels. It can be caused by a combination of certain genetic variations, including ATG16L1, IL23R, IRGM, and NOD2 in chromosome 5 and chromosome 10. As these genes give instructions for making proteins involved in immune system, variations can make the intestine not being able to response to bacteria appeared in the intestinal walls. This can lead to Crohn disease.

2. Ankylosing spondylitis

It is a joint inflammation which affects the spine the most. Symptoms include fatigue, low back pain and stiffness, arthritis in joints. Eventually the bones and spine will fuse together which is called ankylosis. Similar to Crohn disease, ankylosing spondylitis can be caused by combination of genetic variation. The genes include HLA-B, ERAP1, IL1A, and IL23R. However, the variation of genes which cause ankylosing spondylitis still requires further researches and studies.

Reference
1. http://ghr.nlm.nih.gov/gene/IL23R

2. Immunopaedia: http://www.immunopaedia.org.za/index.php?id=472

3. http://www.genego.com/map_2748.php

4. http://ghr.nlm.nih.gov/condition/crohn-disease

5. http://www.cell.com/abstract/S0092-8674(12)01123-3

6. http://www.ccfa.org/what-are-crohns-and-colitis/what-is-crohns-disease/

7. http://www.medicinenet.com/ankylosing_spondylitis/page3.htm#what_are_ankylosing_spondylitis_symptoms_and_signs

8. http://ghr.nlm.nih.gov/condition/ankylosing-spondylitis