Hydrodynamic gene delivery of interleukin-22 protects the mouse liver from concanavalin A-, carbon tetrachloride-, and Fas ligand-induced injury via activation of STAT3.
Interleukin-22 (IL-22) is a recently identified T cell-derived cytokine whose biological significance remains obscure. Previously, we have shown that IL-22 plays a protective role in T cell-mediated hepatitis induced by Concanavalin A (Con A), acting as a survival factor for hepatocytes. In the present paper, we demonstrate that hydrodynamic gene delivery of IL-22 cDNA driven either by a liver-specific albumin promoter or a human cytomegalovirus (CMV) promoter results in IL-22 protein expression, STAT3 activation, and expression of several anti-apoptotic proteins, including Bcl-xL, Bcl-2, and Mcl-1 in the liver. Immunohistochemical analysis reveals that IL-22 protein expression is mainly detected in the cytoplasm of hepatocytes. Overexpression of IL-22 by hydrodynamic gene delivery significantly protects against liver injury, necrosis, and apoptosis induced by administration of Con A, carbon tetrachloride (CCl4), or the Fas agonist Jo-2 mAb. Western blot analyses show that overexpression of IL-22 significantly enhances activation of STAT3 and expression of Bcl-xL, Bcl-2, and Mcl-1 proteins in liver injury induced by Con A. In conclusion, hydrodynamic gene delivery of IL-22 protects against liver injury induced by a variety of toxins, suggesting the therapeutic potential of IL-22 in treating human liver disease.
Pan
Hongna
H
Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
Hong
Feng
F
Radaeva
Svetlana
S
Gao
Bin
B
D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology / Q000517:prevention & control; D003208:Concanavalin A / Q000378:metabolism*; D053222:Fas Ligand Protein; D018014:Gene Transfer Techniques; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000473:pathology / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D048069:Tumor Necrosis Factors / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism; D000097043:Interleukin-22
D002251:Carbon Tetrachloride; D003208:Concanavalin A; D053222:Fas Ligand Protein; D007378:Interleukins; D008562:Membrane Glycoproteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; D048069:Tumor Necrosis Factors; D051020:bcl-X Protein; D000097043:Interleukin-22; C494812:Bcl2l1 protein, mouse; C505661:FASLG protein, human; C505658:Fasl protein, mouse; C579094:Mcl1 protein, mouse