IL-1β/CD14 pathway induces IL-17 production: Dendritic cells activated with IL-1β set Th17 cells on fire by CD14-mediated mechanisms.

I n 2005, the description of a new subset of effector CD4 + T cells called Th17 broke the Th1/Th2 paradigm. Since then, Th17 cells and their eponymous cytokine interleukin (IL)-17 have emerged as central players underlying not only inflammatory and autoimmune processes but also host resistance to several infections. A selected group of pro-inflammatory cytokines including IL-1β, IL-6 and IL-23 has been associated with the development of Th17 cells. 1 IL-1β, in particular, was shown to promote IL-17 production by memory Th17 and γδ T cells, highlighting the tight link between IL-1β and IL-17 immunity. Indeed, mice with genetic ablation of IL-1β or its receptor IL-1R1 showed diminished Th17 development and phenotypes partially overlapping with those of IL-17-deficient mice (that is, reduced inflammation, increased susceptibility to some infections and resistance to autoimmune pathologies). So far, the IL-17-promoting activity of IL-1β has been ascribed to a direct effect on T cells. 2 However, the experimental approaches used did not exclude the possibility that IL-1β may modulate other cells to further trigger IL-17 secretion by T cells. On this issue, Ilarregui et al. 3 describe a novel mechanism by which IL-1β enhances IL-17 production by human memory T cells through indirectly instructing dendritic cells (DCs) to adopt a Th17-promoting program. DCs are undoubtedly the immune cell subset best equipped to sense environmental clues and to induce the best tailored T-cell differentiation program. These cells, together with others of myeloid origin, are able to produce high amounts of IL-1β upon activation with different inflammatory mediators such as microbial ligands of toll-like receptors (TLR), activated complement and other cytokines such as TNF and IL-1β itself. 2 Therefore, the IL-1β putatively present at high concentrations in inflammatory environments could modulate the activation program of the responding DCs in autocrine/ paracrine ways. On the basis of this premise, Ilarregui et al. 3 investigated whether IL-1β could instruct DCs to adopt a Th17-promoting profile. For comparison, these authors used DCs treated with peptidoglycan (PGN), a TLR2/NOD2 agonist well known to induce a Th17-promoting program in antigen presenting cells. 4,5 Conditioning of monocyte-derived DCs with IL-1β resulted in the acquisition of phenotypic and functional features very similar to that observed in PGN-treated DCs, including upregulation of CD14 and expression of high levels of Th17 inducing cytokines (that is, IL-1β, IL-23 and IL-6). Accordingly, IL-1β-treated DCs were almost as efficient as PGN-treated DCs in promotion of IL-17 production …