Regulation of interleukin‐12/interleukin‐23 production and the T‐helper 17 response in humans

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Abstract
Summary: Interleukin‐12 (IL‐12) and IL‐23 share a common chain. Yet, their production in response to pathogens is differentially regulated, and their functions are distinct and often antithetic. IL‐12 is involved in the induction or amplification of the T‐helper (Th) type 1 response, whereas IL‐23 has been associated with the generation of the Th17 response and IL‐17 production. Mycobacterium tuberculosis and yeast zymosan induce IL‐23, but in the absence of other stimuli, no IL‐12 is induced in human dendritic cells (DCs). The stimulation of IL‐23 by M. tuberculosis was mostly explained by the triggering of Toll‐like receptor (TLR2) and the cytoplasmic receptor nucleotide oligomerization domain (NOD)‐containing protein 2, whereas zymosan induces IL‐23 primarily by stimulating the β‐glucan receptor dectin‐1 alone or in combination with TLR2. IL‐23, IL‐6, transforming growth factor (TGF‐β1), and IL‐1β in supernatants from activated human DCs induce human naive CD4+ T cells to produce IL‐17. These data are consistent with various recent reports that TGF‐β is an inducer of IL‐17 production both in human and in mouse cells. However, IL‐1 is necessary in combination with some or all of the other cytokines to induce IL‐17 production in human T cells. The ability of various stimuli to induce Th17 cells depends not only on their induction of IL‐23, IL‐6, and TGF‐β production in DCs but also on their ability to activate directly or indirectly the inflammasome and to induce IL‐1β.