All of the twos, 22-bingo!

IL-22 is currently a hot topic, with researchers generating approximately 400–500 related articles per year. However, articles by Xu et al. and Kulkarni et al. in this issue of JASN are the first to describe the involvement of IL-22 in the kidney.1,2 Interest in IL-22 is growing because of its unique range of cellular targets and the power of its effects,3,4 which are generating increasing excitement about its potential as a therapeutic target.5,6 Unlike other ILs, IL-22 does not interact with leukocytes but instead targets intrinsic tissue cells—principally epithelia, hepatocytes, and some fibroblasts—and is critical for maintaining and restoring them in infection or other types of injury.2,3 The power of these protective effects has been amply demonstrated in injury models in the intestine, lung, and skin; however, until now, there have been no data about its effects in the kidney. The studies by Xu et al. and Kulkarni et al. show that IL-22 provides striking protection from AKI in the ischemiareperfusion injury (IRI) model as well as in recovery after IRI.1,2 These findings help facilitate entirely new approaches to the prevention and management of AKI with the possibility of rapid translation to the clinic, because IL-22 therapy is currently being developed for other diseases and has already entered phase I human trials.7 IL-22 was discovered in 2000, and is a member of the IL-10 cytokine family with highly distinctive properties.8 IL-22 is produced by cells of the innate and adaptive immune systems, including multiple lymphocyte subsets of CD4and CD8-positive T cells, such as T helper 1 (Th1) cells, Th17 cells, and newly characterized Th22 cells; g-d T cells, innate T cells, and natural killer cells; macrophages and dendritic cells; and some subsets of neutrophils.3,4 The generation of IL-22 by T cells is tightly controlled by the cytokine environment, whereas its secretion by macrophages and dendritic cells is more dependent on IL-1 and Tolllike receptors (TLRs).9,10 Once IL-22 is released, it binds to a two-chain receptor composed of IL-22 receptor 1 (IL-22R1), which has high affinity for IL-22, and IL-10 receptor 2, which is essential for signaling. The expression of IL-22R1 is highly restricted and accounts for its biologic effects: It is not expressed by leukocytes but is abundant in epithelial cells in the skin, intestine, and lung, as well as in hepatocytes and the pancreas and in some myofibroblasts.11 The IL-22 receptor signals predominantly through signal transducer and activator of transcription 3 (STAT3), with additional contributions from STAT1 and STAT5, as well as phosphoinositide-3-kinase and mitogen-activated protein kinase.12 IL-22 activity is modulated by IL-22BP, a binding protein that has 20to 1000-fold greater affinity for IL-22 than the IL-22R1.13 IL-22BP is expressed on the surface of immature dendritic cells but is released from them on activation coincident with increased IL-22 expression.14 Although its major activities occur locally, IL-22 can be detected in the circulation and it stimulates hepatocytes to synthesize acute phase reactants in acute inflammatory conditions.15 IL-22 has multiple effects on epithelial cells. Although the details vary from tissue to tissue, these effects can be grouped into three broad categories3,4: (1) strengthening resistance to pathogens by stimulating the generation of antimicrobial proteins (including defensins, S100A family proteins, neutrophil gelatinase–associated lipocalin, and lipocalin) and through the release of selected chemokines; (2) protecting against cell death by increasing expression of antiapoptotic proteins (Bcl2) and decreasing expression of proapoptotic proteins (Bax and Bad); and (3) promoting repair by increasing epithelial cell proliferation and inhibiting terminal differentiation.Multiple studies using deficient mice and pharmacologic manipulation have shown that IL-22 has a major effect on tissue repair in models of acute injury to the intestine, lung, liver, skin, and pancreas.5,6 The protective effects of IL-22 have largely been confined to models of acute injury, but IL-22 also has deleterious effects when secretion by pathogenic T cells contributes to the uncontrolled proliferation of keratinocytes in psoriasis16,17 and synoviocytes in rheumatoid arthritis,18 as well as to tumor progression.19,20 In certain contexts, IL-22 can assume proinflammatory properties.21 The studies by Xu et al. and Kulkarni et al. provide convincing evidence that IL-22 reduces injury in models of ischemiareperfusion in mice. The study by Xu et al. was founded on knowledge of the effects of IL-22 on epithelial injury in other tissues and concentrated on the acute injury after ischemiareperfusion and its modulation by IL-22.1 Interest in IL-22 by Kulkarni et al. arose from a high-throughput in vitro screen for cytokines that enhanced renal tubular epithelial repair, which identified IL-22 as the most promising candidate.2 Consequently, the authors’ subsequent in vivo studies concentrated on tissue repair after IRI. Thus, the two studies are almost completely complementary, although with just enough overlap to reinforce the validity of each study’s conclusions. Published online ahead of print. Publication date available at www.jasn.org.