Parathyroid Hormone–Related Protein Interacts With the Transforming Growth Factor-β/Bone Morphogenetic Protein-2/Gremlin Signaling Pathway to Regulate Proinflammatory and Profibrotic Mediators in Pancreatic Acinar and Stellate Cells. Issue 5 (May 2016)

• Record Type: Journal Article
• Authors: Bhatia, Vandanajay; Cao, Yanna; Ko, Tien C.; Falzon, Miriam
• Is Part Of: Pancreas. Volume 45:Issue 5(2016)
• Publication Date: 2016-05
• Subjects: PTHrP -- TGF-β -- BMP-2 -- gremlin -- acinar cells -- stellate cells; Pancreas -- Diseases -- Periodicals; Pancreas -- Periodicals; Neuroendocrine tumors -- Periodicals; 616.37005
• DOI: 10.1097/MPA.0000000000000522
• Languages: English
• ISSNs: 0885-3177

Abstract

Abstract : Objectives: Transforming growth factor β (TGF-β) regulates immune and fibrotic responses of chronic pancreatitis. The bone morphogenetic protein 2 (BMP-2) antagonist gremlin is regulated by TGF-β. Parathyroid hormone–related protein (PTHrP) levels are elevated in chronic pancreatitis. Here, we investigated the cross-talk between TGF-β/BMP-2/gremlin and PTHrP signaling. Methods: Reverse transcription/real-time polymerase chain reaction, chromatin immunoprecipitation, Western blotting, and transient transfection were used to investigate PTHrP regulation by TGF-β and BMP-2 and gremlin regulation by PTHrP. The PTHrP antagonist PTHrP (7-34) and acinar cells with conditional Pthrp gene deletion (PTHrP Δacinar ) were used to assess PTHrP's role in the proinflammatory and profibrotic effects of TGF-β and gremlin. Results: Transforming growth factor β increased PTHrP levels in acinar cells and pancreatic stellate cells (PSCs) through a Smad3-dependent pathway. Transforming growth factor β's effects on levels of IL-6 and intercellular adhesion molecule 1 (ICAM-1) (acinar cells) and procollagen I and fibronectin (PSCs) were inhibited by PTHrP (7-34). PTHrP Δacinar suppressed TGF-β's effects on IL-6 and ICAM-1. Parathyroid hormone–related hormone increased gremlin in acinar cells, and inhibiting gremlin action suppressed TGF-β's and PTHrP's effects on IL-6 and ICAM-1. Transforming growth factor β–mediated gremlin up-regulation was suppressed in PTHrP Δacinar cells. Bone morphogenetic protein 2 suppressed PTHrP levels in PSCs. Conclusions: Parathyroid hormone–related hormone functions as a novel mediator of the proinflammatory and profibrotic effects of TGF-β. Transforming growth factor β and BMP-2 regulate PTHrP expression, and PTHrP regulates gremlin levels. Abstract : Supplemental digital content is available in the text.