Activation of IL-22 is tightly and directly regulated by an endogenous inhibitor. IL-22 binds to not only a heterodimeric receptor composed of IL-10R2 and IL-22R1 but also a soluble class II cytokine receptor designated IL-22Ra2 (also called IL-22 binding protein, IL-22BP, or CRF2-10). In comparison with IL-22R1, IL-22BP has 20–1000 fold higher affinity to IL-22 [
80‐
82]. Therefore, IL-22BP can strongly inhibit the biological activity of IL-22 in vitro and in vivo by competing with IL-22R1/IL-22 interaction [
12,
80‐
82]. IL-22BP is highly expressed in placenta, spleen, skin, and lung, and to a lesser extent in large and small intestine of humans [
80]. In mouse intestine, DCs [
83], CD4
+ T cells [
84], and epithelial cells [
85] have been proposed as a producer of IL-22BP. The IL-22BP is highly expressed in the normal colon and significantly reduced during acute inflammation induced by DSS [
12,
83,
86]. The inflammation-induced reduction of IL-22BP expression is caused by a formation of inflammasomes that function as a sensor of stress to activate IL-1 and IL-18 [
83] or by the maturation of DCs, suggesting immature DCs as a source of IL-22BP [
86]. In contrast to mice, rather increased expression of intestinal IL-22BP was observed in patients with IBD, and CD4
+ T cells [
84] and eosinophils [
87] have been proposed as the cellular source of IL-22BP. However, more caution may be necessary to evaluate the expression of functional IL-22BP, because there are three functionally different isoforms of IL-22BP in humans but not mice [
88]. Isoform 1, which is composed of six exons, is non-functional due to the lack of secretion. Isoform 2, lacking exon 3, represents a homologue of mouse IL-22BP and possesses a strong inhibitory effect on IL-22 activity. Isoform 3, which lacks exons 3 and 5 and partially exon 6, is most abundantly distributed, but the affinity of isoform 3 to IL-22 is 27-folds lower than that of isoform 2 [
88].
Since IL-22BP expression became rarely detectable during the acute inflammatory response induced by DSS [
12,
83], deficiency of IL-22BP in mice had no significant alteration on the acute inflammation [
83]. Alternatively, supplementation of IL-22BP expression delayed the recovery from this acute inflammation by inhibiting IL-22 activity [
12]. In a chronic colitis model, TNF-α stimulated the IL-22BP expression in CD4
+ T cells, leading to the suppression of IL-22-dependent mucosal healing [
84]. Indeed, anti-TNF-α treatment reduced the expression of IL-22BP in CD4
+ T cells of IBD patients [
84]. Therefore, this finding may provide a clue to further understand the therapeutic mechanism of anti- TNF-α therapy.