Differential IL-23 requirement for IL-22 and IL-17A production during innate immunity against Salmonella enterica serovar Enteritidis.

Early activation of the IL-12/IFN-gamma axis has been shown following Salmonella enterica serovar Enteritidis (S. Enteritidis) infection. We were interested to study whether IL-22 and IL-17A production is initiated early in response to S. Enteritidis. We demonstrate here that IL-22 was strongly elevated in the peritoneal lavage fluid and in serum already 1 day post-intraperitoneal infection (d.p.i.) of mice; not only IL-22 but also IL-17A was produced ex vivo by activated peritoneal exudate cells (PEC). Peritoneal gammadelta T cells were identified as cellular source of IL-17A. The early IL-22 production was completely IL-23-dependent. In contrast, IL-17A production was only partially IL-23-dependent. To investigate the local production of upstream cytokines important for induction of IL-22, IL-17A and IFN-gamma during salmonellosis, the production of IL-23 and IL-12 was studied. Elevated p19 and p40 mRNA levels were found in PEC at 1 d.p.i., whereas p35 mRNA levels were not changed. Besides, the T(h)17-promoting cytokines IL-6, IL-1beta and transforming growth factor-beta were produced in response to S. Enteritidis. However, IL-6 was not required for IL-22 or IL-17A production by PEC. By ex vivo analysis of PEC at 1 d.p.i., we show that the major producers of early IL-12/23p40 in the peritoneal cavity were dendritic cells (DC), whereas macrophages notably contributed to IL-6 production. Taken together, these data suggest that DC initiate early IL-22 production at the site of infection which may contribute to resistance against salmonellosis. Furthermore, we provide evidence that production of IL-22 and IL-17A is differentially regulated during infection.

Maturing dendritic cells are an important source of IL-29 and IL-20 that may cooperatively increase the innate immunity of keratinocytes.

IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29 are new members of the IL-10 interferon family. Monocytes are well-known sources of IL-19, IL-20, and IL-24. We demonstrated here that monocytes also expressed IL-29, and monocyte differentiation into macrophages (Mphi) or dendritic cells (DCs) strongly changed their production capacity of these cytokines. Maturation of DCs with bacterial stimuli induced high expression of IL-28/IL-29 and IL-20. Simulated T cell interaction and inflammatory cytokines induced IL-29 and IL-20 in maturing DCs, respectively. Compared with monocytes, DCs expressed only minimal IL-19 levels and no IL-24. The differentiation of monocytes into Mphi reduced their IL-19 and terminated their IL-20, IL-24, and IL-29 production capacity. Like monocytes, neither Mphi nor DCs expressed IL-22 or IL-26. The importance of maturing DCs as a source of IL-28/IL-29 was supported by the much higher mRNA levels of these mediators in maturing DCs compared with those in CMV-infected fibroblasts, and the presence of IL-28 in lymph nodes but not in liver of lipopolysaccharide-injected mice. IL-19, IL-20, IL-22, IL-24, and IL-26 do not seem to affect Mphi or DCs as deduced from the lack of corresponding receptor chains. The significance of IL-20 and IL-28/IL-29 coexpression in maturing DCs may lie in the broadly amplified innate immunity in neighboring tissue cells like keratinocytes. In fact, IL-20 induced the expression of antimicrobial proteins, whereas IL-28/IL-29 enhanced the expression of toll-like receptors (TLRs) and the response to TLR ligands. However, the strongest response to TLR2 and TLR3 activation showed keratinocytes in the simultaneous presence of IL-20 and IL-29.