Abstract
Pancreatitis is a fibro-inflammatory disorder of the pancreas that can occur acutely or chronically as a result of the activation of digestive enzymes that damage pancreatic cells, which promotes inflammation. Chronic pancreatitis with persistent fibro-inflammation of the pancreas progresses to pancreatic cancer, which is the fourth leading cause of cancer deaths across the globe. Pancreatic cancer involves cross-talk of inflammatory, proliferative, migratory, and fibrotic mechanisms. In this review, we discuss the role of cytokines in the inflammatory cell storm in pancreatitis and pancreatic cancer and their role in the activation of SDF1α/CXCR4, SOCS3, inflammasome, and NF-κB signaling. The aberrant immune reactions contribute to pathological damage of acinar and ductal cells, and the activation of pancreatic stellate cells to a myofibroblast-like phenotype. We summarize several aspects involved in the promotion of pancreatic cancer by inflammation and include a number of regulatory molecules that inhibit that process.
Keywords: Pancreatitis, pancreatic cancer, cytokines, chemokines, immune cell infiltration, inflammation signaling.
Graphical Abstract
[http://dx.doi.org/10.1038/nature14169] [PMID: 25719666]
[http://dx.doi.org/10.1177/1724600817753094] [PMID: 29799354]
[http://dx.doi.org/10.1038/nrdp.2017.60] [PMID: 28880010]
[PMID: 20485254]
[http://dx.doi.org/10.2337/dc08-1755] [PMID: 19208917]
[http://dx.doi.org/10.1159/000092689] [PMID: 16636600]
[http://dx.doi.org/10.2337/diacare.23.10.1592] [PMID: 11023157]
[http://dx.doi.org/10.1093/annonc/mds256]
[http://dx.doi.org/10.1136/gutjnl-2012-302779] [PMID: 23100216]
[http://dx.doi.org/10.1053/j.gastro.2013.01.075] [PMID: 23622137]
[http://dx.doi.org/10.1016/j.cgh.2015.12.040] [PMID: 26772149]
[http://dx.doi.org/10.1016/S0140-6736(10)61852-1] [PMID: 21397320]
[http://dx.doi.org/10.3109/00365529609104990] [PMID: 8865462]
[http://dx.doi.org/10.1053/j.gastro.2009.04.023] [PMID: 19379751]
[http://dx.doi.org/10.1136/gut.2008.155853] [PMID: 19240063]
[http://dx.doi.org/10.1016/j.ejim.2014.08.008] [PMID: 25269432]
[http://dx.doi.org/10.1016/j.ajog.2008.01.003] [PMID: 18359475]
[http://dx.doi.org/10.1038/s41598-018-36266-7] [PMID: 30635594]
[http://dx.doi.org/10.1053/j.gastro.2013.02.007]
[http://dx.doi.org/10.1007/s00125-016-3867-x] [PMID: 26820736]
[http://dx.doi.org/10.1007/s00125-012-2479-3] [PMID: 22327285]
[http://dx.doi.org/10.1111/j.1463-1326.2010.01231.x] [PMID: 20649628]
[http://dx.doi.org/10.3748/wjg.v19.i42.7276] [PMID: 24259958]
[http://dx.doi.org/10.1002/9781119188421.ch62]
[http://dx.doi.org/10.1016/j.bpg.2010.02.007] [PMID: 20510834]
[http://dx.doi.org/10.1016/j.canlet.2013.08.015] [PMID: 23981573]
[http://dx.doi.org/10.1111/imm.13051] [PMID: 30779114]
[http://dx.doi.org/10.3389/fphys.2018.00754] [PMID: 29967585]
[http://dx.doi.org/10.3748/wjg.v22.i2.764] [PMID: 26811623]
[http://dx.doi.org/10.1097/00000658-200201000-00009] [PMID: 11753044]
[http://dx.doi.org/10.1038/ncomms8158] [PMID: 25981357]
[http://dx.doi.org/10.1136/gut.43.2.232] [PMID: 10189850]
[http://dx.doi.org/10.1016/0016-5085(95)90158-2] [PMID: 7539389]
[http://dx.doi.org/10.1053/gast.1997.v112.pm9041259] [PMID: 9041259]
[http://dx.doi.org/10.1097/00006676-200008000-00005] [PMID: 10975706]
[http://dx.doi.org/10.7150/ijbs.3967] [PMID: 22253568]
[PMID: 9393251]
[http://dx.doi.org/10.1158/1078-0432.CCR-08-0157] [PMID: 18676770]
[PMID: 21737619]
[http://dx.doi.org/10.1002/ijc.29445] [PMID: 25604508]
[http://dx.doi.org/10.1038/sj.cgt.7700118] [PMID: 10770643]
[http://dx.doi.org/10.1002/ijc.25437] [PMID: 20473925]
[http://dx.doi.org/10.18632/oncotarget.18185] [PMID: 28915646]
[http://dx.doi.org/10.1084/jem.20141702] [PMID: 25732306]
[http://dx.doi.org/10.1158/1078-0432.CCR-16-0004] [PMID: 27435400]
[http://dx.doi.org/10.3748/wjg.v8.i5.908] [PMID: 12378640]
[http://dx.doi.org/10.1089/cbr.2008.0461] [PMID: 18771346]
[http://dx.doi.org/10.1016/j.cyto.2015.12.003] [PMID: 26868086]
[http://dx.doi.org/10.1136/gut.49.2.251] [PMID: 11454803]
[http://dx.doi.org/10.1189/jlb.0412214] [PMID: 22782966]
[http://dx.doi.org/10.1038/sj.bjc.6602416] [PMID: 15714203]
[PMID: 12097255]
[http://dx.doi.org/10.1053/j.gastro.2007.10.002] [PMID: 18166354]
[http://dx.doi.org/10.1152/ajpgi.00139.2018] [PMID: 30212254]
[http://dx.doi.org/10.1016/j.cellsig.2013.06.004] [PMID: 23770289]
[http://dx.doi.org/10.4049/jimmunol.178.7.4222] [PMID: 17371978]
[http://dx.doi.org/10.1172/JCI64931] [PMID: 23426178]
[http://dx.doi.org/10.1136/gutjnl-2016-311585] [PMID: 27797936]
[http://dx.doi.org/10.1016/j.gastro.2003.07.007] [PMID: 14598258]
[http://dx.doi.org/10.1165/rcmb.2018-0254OC]
[http://dx.doi.org/10.1016/j.celrep.2017.04.052] [PMID: 28514653]
[http://dx.doi.org/10.1159/000452654] [PMID: 27920662]
[http://dx.doi.org/10.1128/IAI.05529-11] [PMID: 22252873]
[http://dx.doi.org/10.1136/gutjnl-2018-317098] [PMID: 30705050]
[http://dx.doi.org/10.1016/j.jaci.2018.12.776]
[http://dx.doi.org/10.1016/j.jaci.2018.02.011] [PMID: 29499224]
[http://dx.doi.org/10.5114/pg.2015.50993] [PMID: 26759626]
[http://dx.doi.org/10.1007/s10555-006-9013-3] [PMID: 17001512]
[http://dx.doi.org/10.1158/1078-0432.CCR-11-0482] [PMID: 21705455]
[http://dx.doi.org/10.4049/jimmunol.178.11.7385] [PMID: 17513789]
[http://dx.doi.org/10.1007/s00011-013-0633-0] [PMID: 23685857]
[http://dx.doi.org/10.1136/gutjnl-2011-300771] [PMID: 22490516]
[http://dx.doi.org/10.18632/oncotarget.13212] [PMID: 27835602]
[http://dx.doi.org/10.1016/j.bbamcr.2014.05.014] [PMID: 24892271]
[http://dx.doi.org/10.1042/BJ20071493] [PMID: 18177271]
[http://dx.doi.org/10.1007/s10555-007-9068-9] [PMID: 17828470]
[http://dx.doi.org/10.1016/j.bbadis.2008.12.002] [PMID: 19111613]
[http://dx.doi.org/10.1016/j.regpep.2006.08.006] [PMID: 17014919]
[http://dx.doi.org/10.1002/path.4555] [PMID: 25950520]
[PMID: 20382594]
[http://dx.doi.org/10.1016/j.canlet.2005.10.041] [PMID: 16458421]
[http://dx.doi.org/10.1016/S1470-2045(16)00078-4] [PMID: 27055731]
[http://dx.doi.org/10.1172/JCI42754] [PMID: 21926469]
[http://dx.doi.org/10.4049/jimmunol.182.3.1746] [PMID: 19155524]
[http://dx.doi.org/10.1073/pnas.1320318110] [PMID: 24277834]
[http://dx.doi.org/10.1158/0008-5472.CAN-08-2155] [PMID: 18974138]
[http://dx.doi.org/10.3892/ijo.30.3.631] [PMID: 17273764]
[http://dx.doi.org/10.1016/j.ejphar.2017.11.019] [PMID: 29162433]
[http://dx.doi.org/10.1016/0167-5699(94)90156-2] [PMID: 8172645]
[http://dx.doi.org/10.1002/ijc.24383] [PMID: 19431209]
[http://dx.doi.org/10.1089/jir.2008.0027] [PMID: 19441883]
[http://dx.doi.org/10.1016/S0016-5085(97)70017-9] [PMID: 9394737]
[http://dx.doi.org/10.1016/S0016-5085(00)70218-6] [PMID: 10648464]
[http://dx.doi.org/10.1136/gut.2004.049403] [PMID: 16284287]
[http://dx.doi.org/10.1053/j.gastro.2011.12.054]
[http://dx.doi.org/10.1158/1078-0432.CCR-13-0525] [PMID: 23653148]
[http://dx.doi.org/10.1016/j.atg.2013.05.004] [PMID: 27942440]
[http://dx.doi.org/10.1067/msy.2000.108613] [PMID: 11056444]
[http://dx.doi.org/10.1038/s41598-018-19643-0] [PMID: 29358632]
[http://dx.doi.org/10.1189/jlb.1204712] [PMID: 15784687]
[http://dx.doi.org/10.3892/ijo.2014.2794] [PMID: 25502147]
[http://dx.doi.org/10.1016/j.bbamcr.2017.02.005] [PMID: 28188806]
[http://dx.doi.org/10.1186/1479-5876-8-45] [PMID: 20459729]
[http://dx.doi.org/10.1093/abbs/gmw101] [PMID: 27797715]
[http://dx.doi.org/10.1016/j.prp.2014.01.001] [PMID: 24629487]
[http://dx.doi.org/10.1083/jcb.141.4.1053] [PMID: 9585422]
[http://dx.doi.org/10.2353/ajpath.2007.061275] [PMID: 17982129]
[http://dx.doi.org/10.1182/blood-2002-03-0841] [PMID: 12393730]
[http://dx.doi.org/10.1002/(SICI)1521-4141(199806)28:06<2025::AID-IMMU2025>3.0.CO;2-C] [PMID: 9645384]
[PMID: 9257816]
[http://dx.doi.org/10.1074/jbc.272.31.19518] [PMID: 9235955]
[http://dx.doi.org/10.1002/(SICI)1521-4141(199805)28:05<1516:AID-IMMU1516>3.0.CO;2-J] [PMID: 9603456]
[http://dx.doi.org/10.1074/jbc.273.12.7118] [PMID: 9507024]
[http://dx.doi.org/10.1007/s00534-011-0395-4] [PMID: 21594558]
[http://dx.doi.org/10.1371/journal.pone.0158529] [PMID: 27505247]
[http://dx.doi.org/10.1016/S0065-230X(10)06003-3] [PMID: 20399957]
[http://dx.doi.org/10.1016/j.cell.2012.04.042] [PMID: 22770218]
[http://dx.doi.org/10.1038/srep33123] [PMID: 27625115]
[http://dx.doi.org/10.1172/JCI86477] [PMID: 27454298]
[http://dx.doi.org/10.1038/nature17403] [PMID: 27049944]
[http://dx.doi.org/10.1016/j.cytogfr.2010.10.011] [PMID: 21111666]
[http://dx.doi.org/10.1080/15384047.2015.1095404] [PMID: 26479470]
[http://dx.doi.org/10.1016/j.trsl.2016.04.006] [PMID: 27183218]
[http://dx.doi.org/10.1097/00004836-200309000-00013] [PMID: 12960727]
[http://dx.doi.org/10.1002/ijc.24040] [PMID: 19035451]
[http://dx.doi.org/10.3748/wjg.v18.i10.1123] [PMID: 22416189]
[http://dx.doi.org/10.3892/ol.2011.300] [PMID: 22848232]
[http://dx.doi.org/10.1182/blood-2009-01-199497] [PMID: 19652202]
[http://dx.doi.org/10.2353/ajpath.2010.081059] [PMID: 20228225]
[http://dx.doi.org/10.1084/jem.166.4.1084] [PMID: 2443596]
[http://dx.doi.org/10.18632/oncotarget.2519] [PMID: 25415223]
[PMID: 20122997]
[http://dx.doi.org/10.12659/MSM.906230] [PMID: 29353287]
[http://dx.doi.org/10.1016/j.pan.2015.01.004] [PMID: 25661686]
[PMID: 18636150]
[http://dx.doi.org/10.1053/j.gastro.2015.02.009] [PMID: 25683115]
[http://dx.doi.org/10.1007/s10620-017-4817-2] [PMID: 29086330]
[http://dx.doi.org/10.1038/bjc.2013.32] [PMID: 23385730]
[http://dx.doi.org/10.1111/j.1476-5381.2011.01225.x] [PMID: 21244370]
[http://dx.doi.org/10.1136/gutjnl-2015-310049] [PMID: 27013602]
[http://dx.doi.org/10.1002/ijc.27990] [PMID: 23233419]
[http://dx.doi.org/10.1053/j.gastro.2011.07.033]
[http://dx.doi.org/10.1084/jem.20111706] [PMID: 22908323]
[http://dx.doi.org/10.1038/labinvest.2013.69] [PMID: 23752129]
[http://dx.doi.org/10.1158/2159-8290.CD-15-1346] [PMID: 27179037]
[http://dx.doi.org/10.1053/hupa.2001.28947] [PMID: 11727255]
[http://dx.doi.org/10.1371/journal.pone.0060529] [PMID: 23555989]
[http://dx.doi.org/10.3748/wjg.v16.i27.3411] [PMID: 20632444]
[http://dx.doi.org/10.1158/1078-0432.CCR-09-1230] [PMID: 20371681]
[http://dx.doi.org/10.1177/039463201402700208] [PMID: 25004833]
[http://dx.doi.org/10.1007/s10238-018-0493-6] [PMID: 29492715]
[http://dx.doi.org/10.1189/jlb.0411195] [PMID: 21810937]
[http://dx.doi.org/10.1038/ncomms10973] [PMID: 26964500]
[http://dx.doi.org/10.1038/ajg.2010.23] [PMID: 20179686]
[http://dx.doi.org/10.1016/B978-0-12-800263-6.00004-5] [PMID: 24938019]
[http://dx.doi.org/10.1155/2012/720768] [PMID: 23227088]
[http://dx.doi.org/10.1016/j.smim.2018.02.001] [PMID: 29428698]
[http://dx.doi.org/10.1007/s00535-017-1390-6] [PMID: 28921377]
[http://dx.doi.org/10.1158/0008-5472.CAN-15-1801-T] [PMID: 26873846]
[http://dx.doi.org/10.3748/wjg.v23.i8.1477] [PMID: 28293095]
[http://dx.doi.org/10.1159/000457788] [PMID: 28611564]
[http://dx.doi.org/10.3892/mco.2016.760] [PMID: 27073662]
[http://dx.doi.org/10.1080/00325481.2017.1246345] [PMID: 27718779]
[http://dx.doi.org/10.1097/CJI.0000000000000062] [PMID: 25415283]
[http://dx.doi.org/10.1158/2326-6066.CIR-14-0215] [PMID: 25678581]
[http://dx.doi.org/10.1097/MPA.0b013e3181577553] [PMID: 18376303]
[http://dx.doi.org/10.1016/S0016-5085(00)70265-4] [PMID: 10702210]
[http://dx.doi.org/10.1016/j.ccr.2012.04.025] [PMID: 22698406]
[http://dx.doi.org/10.1016/S0016-5085(97)70048-9] [PMID: 9136845]
[http://dx.doi.org/10.1111/imm.12746] [PMID: 28419443]
[http://dx.doi.org/10.1155/2012/795026] [PMID: 22536257]
[http://dx.doi.org/10.1016/j.celrep.2017.06.062] [PMID: 28723561]
[http://dx.doi.org/10.1158/2159-8290.CD-15-0843] [PMID: 26715643]
[http://dx.doi.org/10.1158/2159-8290.CD-15-0822] [PMID: 26715642]
[http://dx.doi.org/10.1016/j.pan.2014.02.004] [PMID: 24854615]
[http://dx.doi.org/10.24920/J1001-9242.2007.009] [PMID: 28399987]
[http://dx.doi.org/10.3892/ol.2013.1326] [PMID: 23946775]
[http://dx.doi.org/10.1097/01.sla.0000128681.76786.07] [PMID: 15166955]
[http://dx.doi.org/10.1155/2018/1294951] [PMID: 30622955]
[http://dx.doi.org/10.1016/S1072-7515(02)01222-X] [PMID: 12375755]
[http://dx.doi.org/10.1136/gut.44.2.253] [PMID: 9895386]
[http://dx.doi.org/10.1007/s00535-016-1238-5] [PMID: 27418337]
[http://dx.doi.org/10.1038/sj.bjc.6605968] [PMID: 21045835]
[http://dx.doi.org/10.1186/1476-4598-3-29] [PMID: 14749473]
[http://dx.doi.org/10.1158/1535-7163.MCT-13-0948] [PMID: 24785258]
[http://dx.doi.org/10.1084/jem.20161707] [PMID: 28442553]
[http://dx.doi.org/10.1053/gast.2000.8538] [PMID: 10889171]
[http://dx.doi.org/10.1158/0008-5472.CAN-08-4882] [PMID: 19491262]
[http://dx.doi.org/10.1371/journal.pone.0038721] [PMID: 22761699]
[http://dx.doi.org/10.3892/mmr.2014.2053] [PMID: 24626964]
[http://dx.doi.org/10.1016/j.semcancer.2003.10.003] [PMID: 15246052]
[PMID: 18175225]
[http://dx.doi.org/10.3892/or.16.6.1159] [PMID: 17089032]
[http://dx.doi.org/10.1038/sj.bjc.6604745] [PMID: 19002187]
[http://dx.doi.org/10.1161/ATVBAHA.110.207464] [PMID: 21508344]
[http://dx.doi.org/10.4161/jkst.24053] [PMID: 24069550]
[http://dx.doi.org/10.1155/2017/3415380] [PMID: 28250575]
[http://dx.doi.org/10.1186/s13046-016-0301-7] [PMID: 26847351]
[PMID: 30093939]
[http://dx.doi.org/10.1053/j.gastro.2011.03.041] [PMID: 21439959]
[http://dx.doi.org/10.1016/j.cytogfr.2019.05.003] [PMID: 31126874]
[http://dx.doi.org/10.1016/j.biopha.2017.04.049] [PMID: 28458157]
[http://dx.doi.org/10.1053/j.gastro.2012.09.059] [PMID: 23041324]
[http://dx.doi.org/10.1158/1078-0432.CCR-15-1144] [PMID: 27297583]
[http://dx.doi.org/10.1038/emm.2016.6] [PMID: 26964835]
[http://dx.doi.org/10.1016/j.biocel.2005.12.001] [PMID: 16423553]
[http://dx.doi.org/10.1002/(SICI)1097-0029(19970601)37:5/6<509:AID-JEMT13>3.0.CO;2-U] [PMID: 9220428]
[http://dx.doi.org/10.1097/MOG.0b013e32833d11c6] [PMID: 20625287]
[http://dx.doi.org/10.1016/j.jcmgh.2015.07.006] [PMID: 26693174]
[http://dx.doi.org/10.1172/JCI29882] [PMID: 17525802]
[http://dx.doi.org/10.1155/2016/5272498] [PMID: 26697077]
[http://dx.doi.org/10.1038/nrgastro.2017.12] [PMID: 28270694]
[http://dx.doi.org/10.1172/jci.insight.92282] [PMID: 28679961]
[http://dx.doi.org/10.1158/0008-5472.CAN-16-1986] [PMID: 28249896]
[http://dx.doi.org/10.1136/gut.43.1.128] [PMID: 9771417]
[http://dx.doi.org/10.1073/pnas.1000359107] [PMID: 20852067]
[http://dx.doi.org/10.1172/JCI30082] [PMID: 17200706]
[http://dx.doi.org/10.1136/gut.50.4.535] [PMID: 11889076]
[http://dx.doi.org/10.1084/jem.20142162] [PMID: 26481685]