article · Hepatology
Interleukin-22 helps protect and repair tissues, whereas its natural antagonist, interleukin-22 binding protein, restricts these actions. In individuals suffering from chronic hepatitis C virus or schistosome infections, interleukin-22 provides a protective effect against liver damage. Laboratory tests show that schistosome exposure stimulates interleukin-22 expression and suppresses interleukin-22 binding protein transcripts, with elevated interleukin-22 levels correlating with reduced hepatic fibrosis and lower portal hypertension. Genetic analysis of the gene encoding interleukin-22 binding protein across Chinese, Sudanese, and Brazilian cohorts infected with schistosomes reveals specific variants linked to increased transcript levels and heightened risk of severe fibrosis. These same genetic variants also correlate with increased susceptibility to liver fibrosis and cirrhosis in hepatitis C patients. Consequently, interleukin-22 protects liver tissue, whereas elevated interleukin-22 binding protein worsens disease progression, indicating that targeting this protein could help manage chronic liver damage.
Chronic infections such as hepatitis C and schistosomiasis frequently cause severe liver damage, including fibrosis and cirrhosis. Identifying that interleukin-22 naturally counters liver scarring, while interleukin-22 binding protein worsens it, uncovers a shared biological mechanism across distinct viral and parasitic diseases. This discovery offers crucial insight into why certain patients face severe organ damage and highlights biological targets for developing treatments to halt progressive liver failure.
This work highlights potential drug discovery targets and genetic risk biomarkers for biopharmaceutical developers targeting liver diseases. Interleukin-22 binding protein could serve as a target for therapeutic inhibitors to halt fibrosis and cirrhosis in hepatitis C and schistosomiasis. Furthermore, the identified genetic variants could inform prognostic diagnostic assays to stratify high-risk patients. Because findings rely on laboratory assays and genetic association studies, this research represents an early-stage discovery far from clinical application.
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UNLABELLED: Interleukin (IL)-22 acts on epithelia, hepatocytes, and pancreatic cells and stimulates innate immunity, tissue protection, and repair. IL-22 may also cause inflammation and abnormal cell proliferation. The binding of IL-22 to its receptor is competed by IL-22 binding protein (IL-22BP), which may limit the deleterious effects of IL-22. The role of IL-22 and IL-22BP in chronic liver diseases is unknown. We addressed this question in individuals chronically infected with schistosomes or hepatitis C virus (HCV). We first demonstrate that schistosome eggs stimulate production of IL-22 transcripts and inhibit accumulation of IL22-BP transcripts in schistosome-infected mice, and that schistosome eggs selectively stimulate production of IL-22 in cultures of blood leukocytes from individuals chronically infected with Schistosoma japonicum. High IL-22 levels in cultures correlated with protection against hepatic fibrosis and portal hypertension. To test further the implication of IL-22/IL-22BP in hepatic disease, we analyzed common genetic variants of IL22RA2, which encodes IL-22BP, and found that the genotypes, AA, GG of rs6570136 (P = 0.003; odds ratio [OR] = 2), and CC, TT of rs2064501 (P = 0.01; OR = 2), were associated with severe fibrosis in Chinese infected with S. japonicum. We confirmed this result in Sudanese (rs6570136 GG [P = 0.0007; OR = 8.2], rs2064501 TT [P = 0.02; OR = 3.1]), and Brazilians (rs6570136 GG [P = 0.003; OR = 26], rs2064501 TC, TT (P = 0.03; OR = 11]) infected with S. mansoni. The aggravating genotypes were associated with high IL22RA2 transcripts levels. Furthermore, these same variants were also associated with HCV-induced fibrosis and cirrhosis (rs6570136 GG, GA [P = 0.007; OR = 1.7], rs2064501 TT, TC (P = 0.004; OR = 2.4]). CONCLUSIONS: These results provide strong evidence that IL-22 protects against and IL-22BP aggravates liver fibrosis and cirrhosis in humans with chronic liver infections. Thus, pharmacological modulation of IL-22 BP may be an effective strategy to limit cirrhosis.
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DOI: 10.1002/hep.27629
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