Interleukin 23

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]

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 threw 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.

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]