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.
OBJECTIVE
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) 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 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 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.
From the *Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston; and †Department of Surgery, University of Texas Health Science Center at Houston, Houston, TX.
Vandanajay
V
Bhatia
Yanna
Y
Cao
Tien C
TC
Ko
Miriam
M
Falzon
D061354:Acinar Cells / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D005355:Fibrosis / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D058954:Pancreatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D016207:Cytokines
D055396:Bone Morphogenetic Protein 2; D018836:Inflammation Mediators; D018799:Intercellular Adhesion Molecule-1; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D044162:Parathyroid Hormone-Related Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C113178:Grem1 protein, mouse; D016207:Cytokines