IL-22BP is produced by EOSINOPHILS in HUMAN GUT and INHIBITS the PROTECTIVE ACTIONS of IL-22 during experimental COLITIS

Crohn’s disease and ulcerative colitis, the two major forms of inflammatory bowel diseases (IBDs), are characterized by high levels of IL-22 production. Rodent studies revealed that this cytokine is protective during colitis but whether this is true in IBDs is unclear. In addition, IL-22 is regulated by a potent, specific and soluble inhibitor called interleukin 22-binding protein (IL-22BP), whose regulation has never been assessed in human gut. We show here that levels of IL-22BP are significantly enhanced in the inflamed mucosa of IBDs patients. This was explained by increased numbers of IL-22BP-producing eosinophils that we unexpectedly identify as the most abundant source of IL-22BP protein in both healthy and inflammatory human gut. In addition, using IL-22BP-deficient rats, we confirm that endogenous IL-22BP is effective at blocking protective actions of IL-22 during acute colitis. In conclusion, our study provides new important insights regarding the biology of IL-22 and IL-22BP in the gut and indicates that protective actions of IL-22 are likely to be suboptimal in IBDs thus making IL-22BP a new relevant therapeutic target.