title: Role of parathyroid hormone-related protein in the pro-inflammatory and pro-fibrogenic response associated with acute pancreatitis.
abstract: Pancreatitis is a common and potentially lethal necro-inflammatory disease with both acute and chronic manifestations. Current evidence suggests that the accumulated damage incurred during repeated bouts of acute pancreatitis (AP) can lead to chronic disease, which is associated with an increased risk of pancreatic cancer. While parathyroid hormone-related protein (PTHrP) exerts multiple effects in normal physiology and disease states, its function in pancreatitis has not been previously addressed. Here we show that PTHrP levels are transiently elevated in a mouse model of cerulein-induced AP. Treatment with alcohol, a risk factor for both AP and chronic pancreatitis (CP), also increases PTHrP levels. These effects of cerulein and ethanol are evident in isolated primary acinar and stellate cells, as well as in the immortalized acinar and stellate cell lines AR42J and irPSCc3, respectively. Ethanol sensitizes acinar and stellate cells to the PTHrP-modulating effects of cerulein. Treatment of acinar cells with PTHrP (1-36) increases expression of the inflammatory mediators interleukin-6 (IL-6) and intracellular adhesion protein (ICAM-1), suggesting a potential autocrine loop. PTHrP also increases apoptosis in AR42J cells. Stellate cells mediate the fibrogenic response associated with pancreatitis; PTHrP (1-36) increases procollagen I and fibronectin mRNA levels in both primary and immortalized stellate cells. The effects of cerulein and ethanol on levels of IL-6 and procollagen I are suppressed by the PTH1R antagonist, PTHrP (7-34). Together these studies identify PTHrP as a potential mediator of the inflammatory and fibrogenic responses associated with alcoholic pancreatitis.
authors.affiliation: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Vandanajay
authors.initials: V
authors.lastname: Bhatia
authors.forename: Sung O K
authors.initials: SO
authors.lastname: Kim
authors.forename: Judith F
authors.initials: JF
authors.lastname: Aronson
authors.forename: Celia
authors.initials: C
authors.lastname: Chao
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hellmich
authors.forename: Miriam
authors.initials: M
authors.lastname: Falzon
mesh_terms: D061354:Acinar Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000009:adverse effects; D002108:Ceruletide / Q000009:adverse effects*; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000431:Ethanol / Q000009:adverse effects*; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D012516:Osteosarcoma / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D058954:Pancreatic Stellate Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010195:Pancreatitis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D002492:Central Nervous System Depressants; D024042:Collagen Type I; D005353:Fibronectins; D015850:Interleukin-6; D044162:Parathyroid Hormone-Related Protein; D012333:RNA, Messenger; D018799:Intercellular Adhesion Molecule-1; D000431:Ethanol; D002108:Ceruletide