title: Interferon-γ Decreases Nuclear Localization of Pdx-1 and Triggers β-Cell Dysfunction in Chronic Pancreatitis.
abstract: Interferon-gamma (IFN-γ) is shown to play a major role in β-cell dysfunction in chronic pancreatitis (CP). However, the underlying mechanisms are to be elucidated. The present study was conducted to determine the role of IFN-γ subverting insulin gene expression in CP. Pancreatic tissues from control (n=15) and CP patients (n=30) were analyzed for nuclear localization of pancreatic and duodenal homeobox transcription factor (Pdx-1) after ascertaining their diabetic status. By immunofluorescence and western blot analysis, the influence of IFN-γ, anti-inflammatory cytokine (interleukin-10), and anti-IFN-γ agent epigallocatechin-3-gallate (EGCG) on nuclear localization of Pdx-1was examined in the islets isolated from resected normal pancreatic tissue. Nuclear localization of Pdx-1 was 20.25±2.19 in the islets of diabetic CP patients and 31.44±2.09 in nondiabetic CP patients as compared with controls (60.45±5.11) and the corresponding distribution of Pdx-1 protein in the nuclear compartment was also decreased. Exposure of normal islets to IFN-γ revealed decreased nuclear localization of Pdx-1. Pretreatment with polyphenolic compound EGCG restored the nuclear localization of Pdx-1. These results suggest that IFN-γ induced β-cell dysfunction is mediated through decreased nuclear localization of Pdx-1.
authors.affiliation: 1 Asian Healthcare Foundation , Somajiguda, Hyderabad, India .
authors.forename: Pavan Kumar
authors.initials: PK
authors.lastname: Pondugala
authors.affiliation: 1 Asian Healthcare Foundation , Somajiguda, Hyderabad, India .
authors.forename: M
authors.initials: M
authors.lastname: Sasikala
authors.affiliation: 2 Asian Institute of Gastroenterology , Somajiguda, Hyderabad, India .
authors.forename: Venkat Rao
authors.initials: VR
authors.lastname: Guduru
authors.affiliation: 2 Asian Institute of Gastroenterology , Somajiguda, Hyderabad, India .
authors.forename: Pradeep
authors.initials: P
authors.lastname: Rebala
authors.affiliation: 2 Asian Institute of Gastroenterology , Somajiguda, Hyderabad, India .
authors.forename: D
authors.initials: D
authors.lastname: Nageshwar Reddy
mesh_terms: D002392:Catechin / Q000031:analogs & derivatives / Q000494:pharmacology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D003710:Demography; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology*; D016753:Interleukin-10 / Q000494:pharmacology; D008297:Male; D050500:Pancreatitis, Chronic / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D021381:Protein Transport / Q000187:drug effects; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D007328:Insulin; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D016753:Interleukin-10; D007371:Interferon-gamma; D002392:Catechin; C045651:epigallocatechin gallate