Characterization of the intracellular pathways involved in IL-22 production by dendritic cells

Dendritic cells (DCs) play a key role in the inflammatory process. They participate to the activation of the immune response by a direct cellular contact through receptor-ligand mediated interactions or by the production of specific cytokines able to modulate different cell type activity. In this study, we show that DCs produce the novel cytokine IL-22 in response to TLRs ligands and we studied IL-22 gene transcript modulation both in vitro (Bone Marrow-derived DCs) and in vivo (CD11c+) derived DCs. Several non hematopoietic cells, in particular epithelial cells, express the IL-22 receptor that once induced, stimulates the production of different molecules such as antimicrobial peptides that are active both locally and systemically. Although it is known that innate lymphoid cells are able to produce IL-22 under several conditions and through the activation of different transcription factors, very little it is known about DCs. The ability of DCs to produce IL-22 in response to the activation of TLRs and c-Type lectins receptors has been characterized. DCs derived IL-22 has been shown to induce MYD88-dependent and TRIF-independent pathways. Moreover, the intracellular signalling involved in IL-22 production in DCs has been monitored by using different inhibitors. We found that JNK and ERK MAP kinases play a major role in IL-22 production whereas p38 is not implicated. By blocking the NFkB canonical pathway (p65) with the inhibitor Bay11-7082, we confirmed that it takes part together with AP-1 in IL-22 production. Finally, we tested the role of the aryl hydrocarbon receptor (AhR), as it has been reported to be essential in CD4+cells (Th17 subtype) derived IL-22. The IL-22 gene transcription dependence on AhR has been measured by using agonist and antagonist molecules that confirmed a crucial role for AhR in IL-22 production also in DCs. In conclusion, our study provides the first evidence that DCs are able to produce IL-22 upon TLRs and C-type lectins ligation. IL-22 is known to be expressed in many chronic inflammatory conditions, including psoriasis and rheumatoid arthritis, and its up-regulation often correlates with disease activity. Gaining a better understanding of the IL-22 expression and regulation is important for the development of IL-22 as a potential drug target.