title: Regulation of pancreatic inflammation by connective tissue growth factor (CTGF/CCN2).
abstract: 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- 1b (IL-1b), 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-1b 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-1b 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.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Charrier
authors.forename: Ruju
authors.initials: R
authors.lastname: Chen
authors.forename: Sherri
authors.initials: S
authors.lastname: Kemper
authors.forename: David R
authors.initials: DR
authors.lastname: Brigstock
mesh_terms: D061354:Acinar Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D002108:Ceruletide; D054405:Chemokine CCL3 / Q000378:metabolism; D002633:Chemotaxis; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism*; D017077:Culture Media, Conditioned / Q000378:metabolism; D004195:Disease Models, Animal; D000431:Ethanol; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D046790:Pancreas, Exocrine / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019512:Pancreatitis, Alcoholic / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D050500:Pancreatitis, Chronic / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D061251:Primary Cell Culture; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D054389:Receptors, CCR1 / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
chemical_list: D000943:Antigens, Differentiation; D015415:Biomarkers; C526318:CCN2 protein, mouse; C496534:Ccl3 protein, mouse; D054405:Chemokine CCL3; D017077:Culture Media, Conditioned; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D012333:RNA, Messenger; D054389:Receptors, CCR1; C036763:monocyte-macrophage differentiation antigen; D055513:Connective Tissue Growth Factor; D049452:Green Fluorescent Proteins; D000431:Ethanol; D002108:Ceruletide
references.citation: Crit Rev Clin Lab Sci. 2012 Jan-Feb;49(1):18-31
references.pmid: 22339380
references.citation: Pancreatology. 2010;10(2-3):119-28
references.pmid: 20453549
references.citation: Pancreas. 2012 Apr;41(3):353-7
references.pmid: 22415665
references.citation: DNA Cell Biol. 1997 Sep;16(9):1023-30
references.pmid: 9324304
references.citation: Eur J Immunol. 2011 May;41(5):1203-17
references.pmid: 21523780
references.citation: J Am Soc Nephrol. 2009 Jul;20(7):1513-26
references.pmid: 19423687
references.citation: FASEB J. 2001 Apr;15(6):893-7
references.pmid: 11292648
references.citation: Lab Invest. 2010 Aug;90(8):1179-88
references.pmid: 20368699
references.citation: Exp Cell Res. 1996 Mar 15;223(2):357-71
references.pmid: 8601413
references.citation: Circulation. 2010 Dec 21;122(25):2688-98
references.pmid: 21135363
references.citation: Gastroenterology. 1946 Apr;6:239 passim
references.pmid: 20985701
references.citation: Ann Surg. 2002 Jan;235(1):60-7
references.pmid: 11753043
references.citation: Biol Reprod. 1998 Oct;59(4):828-35
references.pmid: 9746732
references.citation: Mol Hum Reprod. 2006 Jan;12(1):1-6
references.pmid: 16439481
references.citation: Regul Pept. 2011 Jan 17;166(1-3):128-34
references.pmid: 20959124
references.citation: Hepatology. 2009 Sep;50(3):939-47
references.pmid: 19670427
references.citation: Blood. 2000 May 15;95(10):3032-43
references.pmid: 10807766
references.citation: J Neuroinflammation. 2012 Feb 21;9:36
references.pmid: 22353423
references.citation: Cytokine. 2002 Nov 7;20(3):91-106
references.pmid: 12453467
references.citation: J Immunol. 2005 Jun 1;174(11):7341-51
references.pmid: 15905581
references.citation: Reproduction. 2003 Feb;125(2):271-84
references.pmid: 12578541
references.citation: J Immunol. 2010 Mar 15;184(6):3223-32
references.pmid: 20164416
references.citation: Exp Cell Res. 1999 Apr 10;248(1):44-57
references.pmid: 10094812
references.citation: PLoS Pathog. 2010 Feb 26;6(2):e1000661
references.pmid: 20195505
references.citation: J Cell Commun Signal. 2010 Mar;4(1):15-23
references.pmid: 20195389
references.citation: Blood. 2003 Jan 1;101(1):210-5
references.pmid: 12393677
references.citation: Cell Signal. 2008 Oct;20(10):1865-72
references.pmid: 18639630
references.citation: Endocr Rev. 1999 Apr;20(2):189-206
references.pmid: 10204117
references.citation: Glia. 2010 Sep;58(12):1510-21
references.pmid: 20648642
references.citation: Inflamm Res. 2011 Aug;60(8):791-800
references.pmid: 21509626
references.citation: J Biol Chem. 2004 Mar 5;279(10):8848-55
references.pmid: 14684735
references.citation: Int J Biochem Cell Biol. 2004 Oct;36(10):1882-6
references.pmid: 15203102
references.citation: J Cell Commun Signal. 2010 Mar;4(1):1-4
references.pmid: 19798591
references.citation: Gastroenterology. 2008 Oct;135(4):1277-87
references.pmid: 18789941
references.citation: Am J Pathol. 2003 Apr;162(4):1249-58
references.pmid: 12651617
references.citation: Nature. 2003 Oct 30;425(6961):917-25
references.pmid: 14586460
references.citation: Surgery. 1995 Jun;117(6):648-55
references.pmid: 7539942
references.citation: Gut. 2006 Jun;55(6):856-62
references.pmid: 16361307
references.citation: Innate Immun. 2012 Oct;18(5):717-26
references.pmid: 22334618
references.citation: N Engl J Med. 2006 May 18;354(20):2142-50
references.pmid: 16707751
references.citation: Curr Med Chem. 2006;13(23):2737-50
references.pmid: 17073625
references.citation: J Clin Invest. 1998 Apr 15;101(8):1693-8
references.pmid: 9541500