LAUSR

he intestinal epithelial barrier is instrumental in the Tphysical separation of gut microbiota from underlying innate and adaptive immune cells and stromal cells. This “barrier” is anything but static, however, with intestinal stem cells (ISCs) tightly controlling regeneration of the epithelial lining along the crypt–villus axis in a coordinated balance between ISC self-renewal and differentiation into transit-amplifying (TA) cells. Although numerous, welldefined growth factor pathways are known to regulate ISC and TA cell expansion dynamics in the steady state, far less is understood about how specific cytokines expressed during tissue injury and inflammation influence this intricate process. Interleukin (IL)22 is a member of the IL10 family of cytokines, which has received considerable attention because of its pleotropic effects in the intestine. IL22 is expressed constitutively in the small intestine and can be induced in the large intestine during inflammatory conditions. The predominant cell type expressing IL22 in the steady-state intestine appears to be group 3 innate lymphoid cells, although numerous additional cell types including CD4þ (T-helper 17 and T-helper 22 cells), natural killer cells, and neutrophils may produce IL22 during inflammatory conditions. In the intestine, expression of IL22 receptor (IL22R) is restricted mainly to epithelial cells, and signaling via IL22R leads to activation of signal transducer and activator of transcription-3. The IL22/ IL22R axis has been shown to promote intestinal barrier defense by inducing antimicrobial peptides such as members of the regenerating islet-derived protein 3 family (RegIIIb, RegIIIg), S100 calcium-binding protein family (S100A7, S100A8, S100A9), and b-defensin 2. IL22 signaling to intestinal epithelial cells also promotes mucin 1 production and glycosylation, leading to a firmer inner mucus layer. In addition to inducing antimicrobial peptides and the mucus layer, IL22 supports mucosal healing via potently driving epithelial proliferation and regeneration after damage. However, the precise effects of IL22 on the ISC and TA compartments have remained unclear. Two studies from Zwarycz et al and Zha et al recently published in Cellular and Molecular Gastroenterology and Hepatology provide novel insight into the effects of IL22 on intestinal organoids. Both groups independently identified a Janus-faced role for IL22 in enhancing proliferation of TA cells while concomitantly inhibiting ISC expansion. Zwarycz et al first screened for effects of several inflammatory bowel disease (IBD)-related cytokines, including IL-6, IL-17, IL-21, and IL22 on ileal enteroid growth. Using physiological doses of these cytokines based on computational modeling of microenvironment levels, the authors observed that IL-22 was unique in its ability to enhance enteroid size, while