title: IL-22 and IL-22 binding protein (IL-22BP) regulate fibrosis and cirrhosis in hepatitis C virus and schistosome infections.
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.
authors.affiliation: Aix-Marseille Université, UMR_S 906, Marseille, France; Inserm, U906, Marseille, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Sertorio
authors.forename: Xunya
authors.initials: X
authors.lastname: Hou
authors.forename: Rodrigo F
authors.initials: RF
authors.lastname: Carmo
authors.forename: Hélia
authors.initials: H
authors.lastname: Dessein
authors.forename: Sandrine
authors.initials: S
authors.lastname: Cabantous
authors.forename: Mohammed
authors.initials: M
authors.lastname: Abdelwahed
authors.forename: Audrey
authors.initials: A
authors.lastname: Romano
authors.forename: Fernanda
authors.initials: F
authors.lastname: Albuquerque
authors.forename: Luydson
authors.initials: L
authors.lastname: Vasconcelos
authors.forename: Theomira
authors.initials: T
authors.lastname: Carmo
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Arthur
authors.initials: A
authors.lastname: Varoquaux
authors.forename: Violaine
authors.initials: V
authors.lastname: Arnaud
authors.forename: Pablo
authors.initials: P
authors.lastname: Oliveira
authors.forename: Anas
authors.initials: A
authors.lastname: Hamdoun
authors.forename: Hongbin
authors.initials: H
authors.lastname: He
authors.forename: Suzan
authors.initials: S
authors.lastname: Adbelmaboud
authors.forename: Adil
authors.initials: A
authors.lastname: Mergani
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.forename: Ahmed
authors.initials: A
authors.lastname: Monis
authors.forename: Leila Beltrao
authors.initials: LB
authors.lastname: Pereira
authors.forename: Philippe
authors.initials: P
authors.lastname: Halfon
authors.forename: Marc
authors.initials: M
authors.lastname: Bourlière
authors.forename: Raymundo
authors.initials: R
authors.lastname: Parana
authors.forename: Mitermayer
authors.initials: M
authors.lastname: Dos Reis
authors.forename: David
authors.initials: D
authors.lastname: Gonnelli
authors.forename: Patricia
authors.initials: P
authors.lastname: Moura
authors.forename: Nasr Eldin
authors.initials: NE
authors.lastname: Elwali
authors.forename: Laurent
authors.initials: L
authors.lastname: Argiro
authors.forename: Yuesheng
authors.initials: Y
authors.lastname: Li
authors.forename: Alain
authors.initials: A
authors.lastname: Dessein
mesh_terms: D000328:Adult; D000818:Animals; D005260:Female; D019698:Hepatitis C, Chronic / Q000150:complications*; D006801:Humans; D007378:Interleukins / Q000502:physiology*; D008103:Liver Cirrhosis / Q000209:etiology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D018123:Receptors, Interleukin / Q000502:physiology*; D012552:Schistosomiasis / Q000150:complications*; D000097043:Interleukin-22
chemical_list: D007378:Interleukins; D018123:Receptors, Interleukin; D000097043:Interleukin-22; C433253:IL22RA2 protein, human