IL‐22 and IL‐22 binding protein (IL‐22BP) regulate fibrosis ... : Hepatology (original) (raw)

Liver Failure/Cirrhosis/Portal Hypertension

IL‐22 and IL‐22 binding protein (IL‐22BP) regulate fibrosis and cirrhosis in hepatitis C virus and schistosome infections

Sertorio, Mathieu1,2; Hou, Xunya3; Carmo, Rodrigo F.4; Dessein, Hélia1,2; Cabantous, Sandrine1,2; Abdelwahed, Mohammed6,†; Romano, Audrey1,2; Albuquerque, Fernanda7; Vasconcelos, Luydson8; Carmo, Theomira7; Li, Jun3; Varoquaux, Arthur9; Arnaud, Violaine1,2; Oliveira, Pablo1,2,7; Hamdoun, Anas6,†; He, Hongbin3; Adbelmaboud, Suzan6,†; Mergani, Adil10; Zhou, Jie3; Monis, Ahmed6; Pereira, Leila Beltrao8; Halfon, Philippe11; Bourlière, Marc12; Parana, Raymundo13; dos Reis, Mitermayer7; Gonnelli, David14; Moura, Patricia5; Elwali, Nasr Eldin6; Argiro, Laurent1,2; Li, Yuesheng3; Dessein, Alain*,1,2,15

1Aix‐Marseille Université, UMR_S 906MarseilleFrance

2InsermU906MarseilleFrance

3Hunan Institute of Parasitic DiseasesHua‐Ban Qiao Road YueyangChina

4Universidade Federal do Vale do São FranciscoPetrolinaBrazil

5Instituto de Ciencias Biologicas, Universidade PernambucoRecifeBrazil

6Institute of Nuclear MedicineWad MedaniSudan

7Gonçalo Moniz InstituteSalvadorBrazil

8Instituto do FigadoPernambucoRecife

9APHM, CHU Timone, RadiologyMarseilleFrance

10College of Applied Medical SciencesTaif UniversityTurabahSaudi Arabia

11Virology departmentHôpital européenMarseilleFrance

12Hepatology DepartmentHôpital Saint‐JosephMarseilleFrance

13Faculty of MedicineDepartment of MedicineFederal University of BahiaSalvadorBrazil

14APHMLa ConceptionChirurgie plastique et reconstructrice MarseilleFrance

15APHMCHU TimoneMarseilleFrance

*Address reprint requests to: Alain Dessein, M.D., Faculté de Médecine, UMR906, 27 Bd Jean Moulin, 13385 Marseille, France. E‐mail: [email protected]; fax: +33 (0)4 91 32 44 96.

†Drs. Abdelwahed, Hamdoun, and Abdelmaboud contributed to this work, but did not provide a signed author agreement.

Abstract

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. (Hepatology 2015;61:1321–1331)