IL-23 in Infections, Inflammation, Autoimmunity and Cancer: Possible Role in HIV-1 and AIDS

Abstract

The growing family of interleukin (IL)-12-like cytokines produced by activated macrophages and dendritic cells became the important players in the control of infections, development of inflammation, autoimmunity and cancer. However, the role of one of them—heterodimer IL-23, which consists of IL12p40 and the unique p19 subunit in HIV-1 infection pathogenesis and progression to AIDS, represent special interest. We overviewed findings of IL-23 involvement in control of peripheral bacterial pathogens and opportunistic infection, central nervous system (CNS) viral infections and autoimmune disorders, and tumorogenesis, which potentially could be applicable to HIV-1 and AIDS.

Identification and expression analysis of two interleukin-23α (p19) isoforms, in rainbow trout Oncorhynchus mykiss and Atlantic salmon Salmo salar

“…The STATs are subsequently dimerized, phosphorylated, and translocated into the nucleus to activate target genes. In lymphocytes, IL-23 induces a strong phosphorylation of STAT3 and a relatively weak activation of STAT4, whereas the reverse is true for IL-12-induced phosphorylation of STAT3 and STAT4 (Yannam et al, 2012;Tang et al, 2012).…”

“…IL-23 exerts its biological activities through the interaction with the IL-23 receptor complex that is a heterodimer made up of IL-23R (unique for IL-23) and IL-12R␤1 (which in combination with IL-12R␤2 forms the IL-12R) (Yannam et al, 2012). The p40 ␤-chain recruits IL-12R␤1 subunit via site II and induces the p19/IL-23 receptor interaction via site III (Schröder et al, 2015).…”

“…The binding of IL-23 to its receptor complex activates Janus associated kinase (Jak)2 and tyrosine kinase (Tyk)2, resulting in phosphorylation of the receptor complex, and formation of docking sites for several members of the signal transducer and activator of transcription (STAT) (1, 3, 4 and 5) family. The same spectrum of Jak/STAT signalling molecules is also used by IL-12 (Yannam et al, 2012). The STATs are subsequently dimerized, phosphorylated, and translocated into the nucleus to activate target genes.…”

“…IL-23 knockout mice demonstrate impaired bacterial/parasitic clearance, a reduced NK cell number and delayed type hypersensitivity response, and a deficiency in Th cell development. In addition to their effect on Th17 cells, IL-23 also regulates the function of group 3 innate lymphoid cells (ILC3) to produce IL-17 and/or IL-22 (Yannam et al, 2012;Chen et al, 2014). The divergent bioactivity of IL-23 and IL-12 may in part be accounted for by the unique cell type specific expression of the receptor chains, as shown in humans and mice.…”

Impact of p38 mitogen-activated protein kinase inhibition on immunostimulatory properties of human 6-sulfo LacNAc dendritic cells

“…Fibroblast-derived PGE 2 acts in a juxtacrine manner to amplify IL-23 release from DC thus supporting the generation of Th17 responses. The IL-23/Th17 axis is important for the development and maintenance of autoimmune disorders including rheumatoid arthritis, psoriasis and colitis [14][15][16][17]. IL-23 promotes tumour growth directly and indirectly through Th17 responses that drive proliferation, invasion, metastasis and angiogenesis [18][19][20][21][22][23].…”