Salmonella Induced IL-23 and IL-1β Allow for IL-12 Production by Monocytes and Mφ1 through Induction of IFN-γ in CD56+ NK/NK-Like T Cells

Abstract

BackgroundThe type-1 cytokine pathway plays a pivotal role in immunity against intracellular bacterial pathogens such as Salmonellae and Mycobacteria. Bacterial stimulation of pattern recognition receptors on monocytes, macrophages and dendritic cells initiates this pathway, and results in the production of cytokines that activate lymphocytes to produce interferon (IFN)-γ. Interleukin (IL)-12 and IL-23 are thought to be the key cytokines required for initiating a type-1 cytokine immune response to Mycobacteria and Salmonellae. The relative contribution of IL-23 and IL-12 to this process is uncertain.Methodology/Principal FindingsWe show that various TLR agonists induce the production of IL-23 but not IL-12 in freshly isolated human monocytes and cultured human macrophages. In addition, type 1 pro-inflammatory macrophages (Mϕ1) differentiated in the presence of GM-CSF and infected with live Salmonella produce IL-23, IL-1β and IL-18, but not IL-12. Supernatants of Salmonella-infected Mϕ1 contained more IL-18 and IL-1β as compared with supernatants of Mϕ1 stimulated with isolated TLR agonists, and induced IFN-γ production in human CD56+ cells in an IL-23 and IL-1β-dependent but IL-12-independent manner. In addition, IL-23 together with IL-18 or IL-1β led to the production of GM-CSF in CD56+ cells. Both IFN-γ and GM-CSF enhanced IL-23 production by monocytes in response to TLR agonists, as well as induced IL-12 production.Conclusions/SignificanceThe findings implicate a positive feedback loop in which IL-23 can enhance its release via induction of IFN-γ and GM-CSF. The IL-23 induced cytokines allow for the subsequent production of IL-12 and amplify the IFN-γ production in the type-1 cytokine pathway.

Priming of Human Resting NK Cells by Autologous M1 Macrophages via the Engagement of IL-1β, IFN-β, and IL-15 Pathways

“…Indeed, although the relatively low NK cell expression of IL-1RI, as compared with ILCs, has led to the general consensus that NK cells are negative for this receptor (30), our findings are in line with previous reports showing that human NK cells express detectable levels of IL-1RI and that IL-1b has biological activities on human NK cells (28,29,31). In particular, it has been also reported that IL-1b acts as a synergistic cytokine with IL-12, IL-15, and IL-23 for IFN-g production (28,31,32) and, to the best of our knowledge, this study reports for the first time that IL-1b also increases human NK cell cytotoxicity via the induction of NKp44 expression. Indeed, our results demonstrate that: 1) M1-primed NK cells have a significantly higher expression of IL-1RI compared with their resting counterparts; 2) the incubation of NK cells in vitro with rhIL-1 upregulated NKp44; 3) the masking of IL-1b and IL-1RI decreased NKp44 expression on M1-primed NK cells; and 4) the use of the inflammasome inhibitor glibenclamide inhibited M1 production of IL-1b, thus preventing the M1-induced upregulation of NKp44.…”

Natural Killer (NK) Cells in Antibacterial Innate Immunity: Angels or Devils?

“…Furthermore, these chemokines enhance the cytolytic (123). Salmonella was also shown to induce the production of IL-1β and IL-23 by macrophages favoring the production of IFN-γ by NK cells (124). A similar synergy between IL-1β and IL-12 leading to an enhanced production of IFN-γ was also reported in response to LPS and L. monocytogenes (109).…”

IFN‐λ‐mediated IL‐12 production in macrophages induces IFN‐γ production in human NK cells

“…Previous publications have also described a role for IL-12-related cytokines in macrophage-NK cell interactions. Specifically, macrophage-derived expression of IL-23 and IL-27 induced the production of IFN-γ and GM-CSF in NK cells [31][32][33]. Although the production of IL-27 was monitored in IFN-λ-stimulated macrophages, the effects on NK-cell function were not explored in this study.…”