IL-12 and IL-23—Close Relatives with Structural Homologies but Distinct Immunological Functions

Abstract

Cytokines of the IL-12 family show structural similarities but have distinct functions in the immune system. Prominent members of this cytokine family are the pro-inflammatory cytokines IL-12 and IL-23. These two cytokines share cytokine subunits and receptor chains but have different functions in autoimmune diseases, cancer and infections. Accordingly, structural knowledge about receptor complex formation is essential for the development of new therapeutic strategies preventing and/or inhibiting cytokine:receptor interaction. In addition, intracellular signaling cascades can be targeted to inhibit cytokine-mediated effects. Single nucleotide polymorphisms can lead to alteration in the amino acid sequence and thereby influencing protein functions or protein–protein interactions. To understand the biology of IL-12 and IL-23 and to establish efficient targeting strategies structural knowledge about cytokines and respective receptors is crucial. A highly efficient therapy might be a combination of different drugs targeting extracellular cytokine:receptor assembly and intracellular signaling pathways.

Oxyresveratrol Inhibits R848-Induced Pro-Inflammatory Mediators Release by Human Dendritic Cells Even When Embedded in PLGA Nanoparticles

“…It is worth to emphasize that here we show that oxyresveratrol inhibited the R848-induced secretion of cytokines which play a fundamental role in activation of the inflammatory process. In fact, IL-12 stimulates T cells and natural killer cells to produce IFN-γ, which in turn widens the immune and inflammatory response [ 4 , 5 , 35 ], TNF-α mediates basal inflammatory events such as edema, leukocyte adhesion to epithelium, oxidative stress, and fever [ 6 ], and IL-6 activates, among others, acute phase responses, B lymphocyte maturation, and T cell functions [ 7 ]. Therefore, oxyresveratrol might be a useful tool to treat autoimmune and chronic inflammatory diseases, such as inflammatory bowel diseases, psoriasis, ankylosing spondylitis, multiple sclerosis, asthma, Crohn’s disease, ulcerative colitis, Alzheimer’s diseases and rheumatoid arthritis, in which IL-12, TNF-α, and IL-6 have been found to play an important role [ 7 , 36 , 37 , 38 , 39 ].…”

“…However, the inclusion of oxyresveratrol into PLGA nanoparticles had an inhibitory effect on this synergistic mechanism, making the nanoparticles less dangerous. These data, although limited to IL-12, IL-6 and TNF-α, which are anyway fundamental mediators of inflammation [ 4 , 5 , 6 , 7 ], indicate that oxyresveratrol, in addition to carrying out an anti-inflammatory effect on virus-stimulated DCs, once inserted into particles can render them more biocompatible. In conclusion here we show that oxyresveratrol represents a useful molecule to inhibit the activity of human DCs.…”

“…Mature DCs produce chemical mediators that modulate the adaptive immune reaction and the inflammatory process to fight cancer cells and pathogen microorganisms. Among the most important mediators secreted by DCs there is IL-12, a fundamental cytokine activating natural killer cells and T lymphocytes [ 4 , 5 ], as well as IL-6 and TNF-α that stimulate the immune cells and are involved in the induction of the systemic acute phase reaction characterized by fever, headache, changes in the sleep-wake cycle, anorexia, nausea and emesis [ 6 , 7 ]. Therefore DCs play a fundamental role in regulating both inflammatory and adaptive immune response, and a decreased tolerogenic activity of these cells can promote pathological events such as hypersensitivity and autoimmunity [ 8 , 9 ].…”

From Science to Success? Targeting Tyrosine Kinase 2 in Spondyloarthritis and Related Chronic Inflammatory Diseases

“…The STAT specificity of a given cytokine receptor is driven not by the JAKs themselves, but by the peptide sequence of the cytokine receptor’s intracellular domain providing a docking site for a given STAT ( Stahl et al, 1995 ; Naeger et al, 1999 ). For example the IL-12RB2 binds STAT4, while IL-23R binds STAT3 ( Teng et al, 2015 ; Floss et al, 2020 ). While a given cytokine receptor preferentially induces the activation of selected STATs, there is no clear understanding of what role the specific receptor-associated JAKs play in activating a given STAT.…”

Probing the Binding of Interleukin-23 to Individual Receptor Components and the IL23 Heteromeric Receptor Complex in Living Cells Using NanoBRET

“…The specific receptor for the IL-23 cytokine is formed of the IL-12 receptor subunit b1 (IL12Rb1) and the IL-23 receptor (IL23R), which are both needed for subsequent Janus kinase (JAK) activation and signaling (Parham et al, 2002). The formation of heteromers by IL-12 family cytokine receptors facilitates promiscuous pairing within the IL-12 family, leading to a diverse range of functional effects (Floss et al, 2020;Hasegawa et al, 2016). The archetypal example of this promiscuity is the dual use of the IL12p40 cytokine subunit and the IL12Rb1 receptor subunit in both the IL-23 and IL-12 cytokine receptor complexes (Parham et al, 2002).…”