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.
Highlights
Cytokines are important mediators of the immune system
This review focuses on structural features of IL-12 and IL-23, cytokine:receptor complex formation, signal transduction and functional consequences of single nucleotide polymorphisms (SNPs) within
This review focuses on molecular and structural features of IL-12 type cytokines and their cognate receptors
Summary
Cytokines are important mediators of the immune system. They are involved in pathophysiological processes including autoimmunity and cancer development. Active IL-23 requires secretion of IL-12p40 and IL-23p19 [9,68] Both subunits are linked via an intersubunit disulfide bond formed at the top edge of the interface between human IL-23p19 C73 on the A-B loop to IL-12p40 C199 [70] (Figure 2B,C). IL-23p19 was sufficient to prevent signaling of cells expressing murine IL-23 receptors, indicating differences in the binding interface of human and murine IL-23 receptor complexes [90]. Single amino acid substitutions Y185R and Y189R prevented binding of IL-12 to murine and human receptors, respectively, and influenced signal transduction. This mechanistic interaction paradigm segregates cognate and shared receptor binding to α and β subunits of the heterodimeric IL-12 cytokine family
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