Interleukin-22 Induces Interleukin-18 Expression from Epithelial Cells during Intestinal Infection

Abstract

T helper 1 (Th1) cell-associated immunity exacerbates ileitis induced by oral Toxoplasma gondii infection. We show here that attenuated ileitis observed in interleukin-22 (IL-22)-deficient mice was associated with reduced production of Th1-cell-promoting IL-18. IL-22 not only augmented the expression of Il18 mRNA and inactive precursor protein (proIL-18) in intestinal epithelial cells after T. gondii or Citrobacter rodentium infection, but also maintained the homeostatic amount of proIL-18 in the ileum. IL-22, however, did not induce the processing to active IL-18, suggesting a two-step regulation of IL-18 in these cells. Although IL-18 exerted pathogenic functions during ileitis triggered by T. gondii, it was required for host defense against C. rodentium. Conversely, IL-18 was required for the expression of IL-22 in innate lymphoid cells (ILCs) upon T. gondii infection. Our results define IL-18 as an IL-22 target gene in epithelial cells and describe a complex mutual regulation of both cytokines during intestinal infection.

Deciphering the crosstalk among IL-1 and IL-10 family cytokines in intestinal immunity

“…Recent studies have highlighted a complex mucosal cytokine network dependent on crosstalk between leukocytes, epithelial cells, and microbiota signals, notably the regulation of IL-22 by IL-1 family cytokines [46,47]. As discussed above, TH17 cells and TH22 cells are the dominant IL-22 producers among the different TH subsets.…”

“…IL-23 and IL-18 can augment IL-17 production through a Stat4-dependent mechanism in vitro [64]. In vitro IL-18 also acts on differentiated TH17 and TH22 cells to promote IL-22 production [47] (Figure 1). Importantly, induction of IL-22 in the ileum after Toxoplasma gondii infection is compromised in IL-18-deficient mice, supporting a crucial role of IL-18 in IL-22 regulation in vivo [11].…”

Inflammasomes of the intestinal epithelium

“…IL-18 also downregulates IL-22-binding protein expression in lamina propria dendritic cells [76] and synergizes with IL-23 to promote IL-22 expression by innate lymphoid cells [77]. The elevated levels of IL-22 act on IECs to enhance antimicrobial responses, fortify the epithelial barrier [78], and notably also promote pro-IL-18 expression by IECs both at steady state and upon infection [77].…”

“…The elevated levels of IL-22 act on IECs to enhance antimicrobial responses, fortify the epithelial barrier [78], and notably also promote pro-IL-18 expression by IECs both at steady state and upon infection [77]. Although the mucosal IL-18-IL-22 loop drives protective epithelial barrier responses and wound healing, excessive activation of this circuit is associated with pathological inflammatory responses to Toxoplasma gondii and promotion of intestinal tumorigenesis [76,77]. Taken together, recent studies place IL-18 and IL-22 at the center of an IEC-leukocyte circuit that regulates mucosal immunity, inflammation, and epithelial repair.…”

Profile of interleukin-22 in gut mucosal health and disease

“…Recent data also suggest a reciprocal relationship between IL-18 and IL-22, with the former able to regulate IL-22 expression in the ileum and the latter inducing IL-18 during Toxoplasma gondii infection. 67 Conversely, several cytokines have been implicated in the suppression of IL-22 production, although the underlying mechanisms differ. Thus, IL-25 may indirectly target IL-22 production by suppressing the production of IL-23.…”