David R. Brigstock1,2,3,* 2014. Immunology 141:564-576.
Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
Molecular, Cellular and Developmental Biology Program, The Ohio State University, Columbus, OH, USA
Department of Surgery, The Ohio State University, Columbus, OH, USA
* Correspondence: David R. Brigstock, Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Room WA2011, 700 Children's Drive, Columbus, OH 43205, USA. Email: David.Brigstock@NationwideChildrens.Org Senior author: David R. Brigstock
Pancreatitis is caused by long-term heavy alcohol consumption, which results in injury and death of pancreatic acinar cells (PAC). The PAC play a pivotal role in mediating early inflammatory responses but the underlying mechanisms remain poorly understood. Treatment of C57BL/6 mice with ethanol and cerulein resulted in increased staining for acinar interleukin-1β (IL-1β), chemokine (C-C motif) ligand 3 (CCL3), or connective tissue growth factor (CTGF/CCN2) by Day 16 and this was associated with increased infiltration of F4/80-positive macrophages and increased expression of pancreatic CTGF/CCN2 mRNA. Compared with wild-type Swiss Webster mice, ethanol treatment of pan-green fluorescent protein (GFP)-CTGF/CCN2 transgenic mice caused enhanced acinar staining for GFP or CTGF/CCN2 and a significant increase in pancreatic infiltration of F4/80-positive macrophages or NIMP-R14-positive neutrophils. Treatment of primary mouse PAC or the rat AR42J PAC line with ethanol or CTGF/CCN2 resulted in enhanced expression of IL-1β or CCL3. Conditioned medium from CTGF/CCN2-treated AR42J cells induced chemotaxis in NR8383 macrophages and this response was abrogated in a dose-dependent manner by addition of BX471, an inhibitor of chemokine (C-C motif) receptor 1. These results reveal that acinar CTGF/CCN2 plays a novel role in alcohol-induced inflammatory processes in the pancreas by increasing infiltration of macrophages and neutrophils and increasing acinar production of inflammatory mediators such as IL-1β or CCL3. The early production of CTGF/CCN2 by PAC to drive inflammation is distinct from its previously reported production by pancreatic stellate cells to drive fibrosis at later stages of pancreatic injury.
*Note: The Normal Chicken IgY used in this publication was produced by Gallus Immunotech Inc.