Interleukin 23

Interleukin-23 (IL-23) is a heterodimeric cytokine composed of an IL12B (IL-12p40) subunit (that is shared with IL12) and the IL23A (IL-23p19) subunit.[1] IL-23 is part of IL-12 family of cytokines.[2] A functional receptor for IL-23 (the IL-23 receptor) has been identified and is composed of IL-12R β1 and IL-23R.[3] Adnectin-2 is binding to IL-23 and compete with IL-23/IL-23R.[4] mRNA of IL-23R is 2,8 kB in length and includes 12 exons. The translated protein contains 629 amino acids, which is a type I penetrating protein includes signal peptide, an N-terminal fibronectin III-like domain and an intracellular part contains 3 potential tyrosine phosphorylation domains.[5] There are 24 variants of splicing of IL-23R in mitogen-activated lymphocytes.[6] IL-23R has some single nucleotide polymorphisms in the domain of binding IL-23 so there can be differences in activation of Th17.[7] There is also variant of IL-23R which has just extracellular part and it´s known as soluble IL-23R. This form can compete with membrane form to bind IL-23 and there can be difference in activation of Th17 immune response and regulation of inflammation and immune function.[8]

IL12B
Crystal structure of IL-12B
Identifiers
SymbolIL12B
Alt. symbolsCLMF2, NKSF2, p40
NCBI gene3593
HGNC5970
OMIM161561
PDB1F42
RefSeqNM_002187
UniProtP29460
Other data
LocusChr. 5 q31.1-33.1
interleukin 23, alpha subunit p19
Identifiers
SymbolIL23A
NCBI gene51561
HGNC15488
RefSeqNM_016584
Other data
LocusChr. 12 q13.13

Discovery

IL-23 was first described by Robert Kastelein and colleagues at the DNAX research institute using a combination of computational, biochemical and cellular immunology approaches.[1]

Function

IL-23 is a proinflammatory cytokine. IL-23 has been shown to be a key cytokine for Th17 maintenance and expansion. Th17 are polarised by IL-6 and TGF-β which activate Th17 transcription factor RORγt. IL-23 stabilises RORγt and thus enables Th17 to properly function and release their effector cytokines such as IL-17, IL-21, IL-22 and GM-CSF which mediate protection against extracellular parasites (fungi and bacteria) and participate in barrier immunity.[9] Similar effects as IL-23 has on Th17 cells were described on type 3 innate lymphoid cells which actively secrete Th17 cytokines upon IL-23 stimulation.[10] NK cells express IL-23 receptor too. They respond with increased IFN-γ secretion and enhanced antibody-dependent cellular cytotoxicity. IL-23 also induces proliferation of CD4 memory T cells (not naïve cells).[11] Along with mentioned proinflammatory effects IL-23 promotes angiogenesis.[12] 

IL-23 is mainly secreted by activated dendritic cells, macrophages or monocytes. Innate lymphoid cells and also gamma delta T cells also produce IL-23.[2] B cells produces IL-23 through BCR signaling.[13] Secretion is stimulated by an antigen stimulus recognised by a pattern recognition receptor.[14] IL-23 imbalance and increase is associated with autoimmune and cancerous diseases. It is thus a target for therapeutic research.[9] IL-23 expressed by dendritic cells is further induced by thymic stromal lymphopoietin – a proallergic cytokine expressed by keratinocytes which is elevated in psoriatic lesions. So inhibition of this cytokine can be potential therapeutic option for patients with psoriasis by decreasing dendritic cells activation and thereby reduction of IL-23.[15] Dermal dendritic cells are in contact with nociceptive neurons and if they are pharmacologically canceled there will be no dendritic cells to produce IL-23. If there is no IL-23 there will not be also inflammatory cells in the skin of psoriatic patients.[16] IL-23 is also elevated during bacterial meningitis. This production makes epithelial dysregulation and inflammation.[17]

Prior to the discovery of IL-23, IL-12 had been proposed to represent a key mediator of inflammation in mouse models of inflammation.[18] However, many studies aimed at assessing the role of IL-12 had blocked the activity of IL-12p40, and were therefore not as specific as thought. Studies which blocked the function of IL-12p35 did not produce the same results as those targeting IL-12p40 as would have been expected if both subunits formed part of IL-12 only.[19] Also Mycobacterium avium subspecies paratuberculosis stimulated monocyte-derived macrophages are one of the contributors of IL-23. Cows with Johne´s disease had elevated IL-23.[20]

The discovery of an additional potential binding partner for IL-12p40 led to a reassessment of this role for IL-12. Seminal studies in experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis, showed that IL-23 was responsible for the inflammation observed, not IL-12 as previously thought.[21] Subsequently, IL-23 was shown to facilitate development of inflammation in numerous other models of immune pathology where IL-12 had previously been implicated including models of arthritis,[22] intestinal inflammation,[23][24][25] and psoriasis.[26] Low concentrations of IL-23 support lung tumor growth and high concentrations of IL-23 inhibit proliferation of lung cancer cells.[27] IL-23 and IL-23R were identified in serum of non-small cell lung cancer patients and they can be potential prognostic serum marker.[28] IL-23 can also make progression of cardiovascular disease as atherosclerosis, hypertension, aortic dissection, cardiac hypertrophy, myocardial infarction and acute cardiac injury.

Monoclonal antibodies - drugs

IL-23 is one of the therapeutic targets to treat the inflammatory diseases.[4] Ustekinumab, a monoclonal antibody directed against this cytokine, is used clinically to treat certain autoimmune conditions.[29] Guselkumab is also monoclonal antibody against IL-23. Blocking IL-23 can slow clinical manifestation of psoriasis indirectly affecting Th17 immune response and producting of IL-17.[30] For treating of psoriasis is better to use ixekizumab which is IL-17A antagonist because its faster than guselkumab, tildrakizumab or riskankizumab which are inhibitors of p19 of IL-23.[31] Risankizumab has the best treatment results for psoriasis in comparison with other IL-23 inhibitors.[32]

Signalling

IL-23 heterodimer binds the receptor complex - p19 subunit binds IL-23R while p40 subunit binds IL-12RB1 which leads to recruitment of Janus kinase 2 and Tyrosine kinase 2 kinases. Janus kinase 2 and Tyrosine kinase 2 transduce the signal and phosphorylate STAT3 and STAT4. STATs dimerise and activate transcription of target genes in nucleus. STAT3 is responsible for key Th17 development attributes like RORγt expression or transcription of Th17 cytokines.[9] In brain, IL-23 is able to activate γδT cells to overexpress IL-17, which contributes to the inflammatory response and thus plays a key role in secondary brain injury after spontaneous intracerebral hemorrhage.[33]

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gollark: Also IPFS.
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gollark: Why are you running a public filehost site? Either nobody will use it or your thing will immediately implode with bad.
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References
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