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https://www.arca.fiocruz.br/handle/icict/15197
IL-22 AND IL-22 BINDING PROTEIN (IL-22BP) REGULATE FIBROSIS AND CIRRHOSIS IN HEPATITIS C VIRUS AND SCHISTOSOME INFECTIONS
Interleukins
Liver cirrhosis
Adult
Humans
Schistosomiasis
Receptors, interleukin
Author
Sertorio, Mathieu
Hou, Xunya
Carmo, Rodrigo F
Dessein, Hélia
Cabantous, Sandrine
Abdelwahed, Mohammed
Romano, Audrey
Albuquerque, Fernanda
Vasconcelos, Luydson
Carmo, Theomira Mauadie de Azevedo
Li, Jun
Varoquaux, Arthur
Arnaud, Violaine
Oliveira, Pablo
Hamdoun, Anas
He, Hongbin
Adbelmaboud, Suzan
Mergani, Adil
Zhou, Jie
Monis, Ahmed
Pereira, Leila Beltrao
Halfon, Philippe
Bourlière, Marc
Parana, Raymundo
Reis, Mitermayer Galvão dos
Gonnelli, David
Moura, Patricia
Elwali, Nasr Eldin
Argiro, Laurent
Li, Yuesheng
Dessein, Alain
Hou, Xunya
Carmo, Rodrigo F
Dessein, Hélia
Cabantous, Sandrine
Abdelwahed, Mohammed
Romano, Audrey
Albuquerque, Fernanda
Vasconcelos, Luydson
Carmo, Theomira Mauadie de Azevedo
Li, Jun
Varoquaux, Arthur
Arnaud, Violaine
Oliveira, Pablo
Hamdoun, Anas
He, Hongbin
Adbelmaboud, Suzan
Mergani, Adil
Zhou, Jie
Monis, Ahmed
Pereira, Leila Beltrao
Halfon, Philippe
Bourlière, Marc
Parana, Raymundo
Reis, Mitermayer Galvão dos
Gonnelli, David
Moura, Patricia
Elwali, Nasr Eldin
Argiro, Laurent
Li, Yuesheng
Dessein, Alain
Affilliation
Aix-Marseille Universit e. Marseille, France / Inserm. Marseille, France
Hunan Institute of Parasitic Diseases. Hua-Ban Qiao Road Yueyang. China
Universidade Federal do Vale do São Francisco. Petrolina, Brasil
Aix-Marseille Universit e. Marseille, France / Inserm. Marseille, France
Aix-Marseille Universit e. Marseille, France / Inserm. Marseille, France
Institute of Nuclear Medicine. Wad Medani, Sudan
Aix-Marseille Universit e. Marseille, France / Inserm. Marseille, France
Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil
Instituto do Figado. Recife, PE, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil
Hunan Institute of Parasitic Diseases. Hua-Ban Qiao Road Yueyang. China
APHM. CHU Timone, Radiology. Marseille, France
Aix-Marseille Universit e. Marseille, France / Inserm. Marseille, France
Aix-Marseille Universit e. Marseille, France / Inserm. Marseille, France / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil
Institute of Nuclear Medicine. Wad Medani, Sudan
Hunan Institute of Parasitic Diseases. Hua-Ban Qiao Road Yueyang. China
Institute of Nuclear Medicine. Wad Medani, Sudan
Taif University. College of Applied Medical Sciences. Turabah, Saudi Arabia
Institute of Nuclear Medicine. Wad Medani, Sudan
Institute of Nuclear Medicine. Wad Medani, Sudan
Instituto do Figado. Recife, PE, Brasil
Hôpital Europeen. Virology Department. Marseille, France
Hôpital Saint-Joseph. Hepatology Department. Marseille, France
Federal University of Bahia. Faculty of Medicine. Department of Medicine.
Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil
APHM. La Conception, Chirurgie plastique et reconstructrice. Marseille, France
Universidade Pernambuco. Instituto de Ciencias Biologicas. Recife, PE, Brasil
Institute of Nuclear Medicine. Wad Medani, Sudan
Aix-Marseille Universite. Marseille, France / Inserm. Marseille, France
Hunan Institute of Parasitic Diseases. Hua-Ban Qiao Road Yueyang. China
Aix-Marseille Universite. Marseille, France / Inserm. Marseille, France / APHM. CHU Timone. Marseille, France
Hunan Institute of Parasitic Diseases. Hua-Ban Qiao Road Yueyang. China
Universidade Federal do Vale do São Francisco. Petrolina, Brasil
Aix-Marseille Universit e. Marseille, France / Inserm. Marseille, France
Aix-Marseille Universit e. Marseille, France / Inserm. Marseille, France
Institute of Nuclear Medicine. Wad Medani, Sudan
Aix-Marseille Universit e. Marseille, France / Inserm. Marseille, France
Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil
Instituto do Figado. Recife, PE, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil
Hunan Institute of Parasitic Diseases. Hua-Ban Qiao Road Yueyang. China
APHM. CHU Timone, Radiology. Marseille, France
Aix-Marseille Universit e. Marseille, France / Inserm. Marseille, France
Aix-Marseille Universit e. Marseille, France / Inserm. Marseille, France / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil
Institute of Nuclear Medicine. Wad Medani, Sudan
Hunan Institute of Parasitic Diseases. Hua-Ban Qiao Road Yueyang. China
Institute of Nuclear Medicine. Wad Medani, Sudan
Taif University. College of Applied Medical Sciences. Turabah, Saudi Arabia
Institute of Nuclear Medicine. Wad Medani, Sudan
Institute of Nuclear Medicine. Wad Medani, Sudan
Instituto do Figado. Recife, PE, Brasil
Hôpital Europeen. Virology Department. Marseille, France
Hôpital Saint-Joseph. Hepatology Department. Marseille, France
Federal University of Bahia. Faculty of Medicine. Department of Medicine.
Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil
APHM. La Conception, Chirurgie plastique et reconstructrice. Marseille, France
Universidade Pernambuco. Instituto de Ciencias Biologicas. Recife, PE, Brasil
Institute of Nuclear Medicine. Wad Medani, Sudan
Aix-Marseille Universite. Marseille, France / Inserm. Marseille, France
Hunan Institute of Parasitic Diseases. Hua-Ban Qiao Road Yueyang. China
Aix-Marseille Universite. Marseille, France / Inserm. Marseille, France / APHM. CHU Timone. Marseille, France
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.
Keywords
Hepatitis CInterleukins
Liver cirrhosis
Adult
Humans
Schistosomiasis
Receptors, interleukin
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