Effect of JAK2/STAT3 signaling pathway on liver injury associated with severe acute pancreatitis in rats

Li,Minli; Zhang,Xiaohua; Wang,Bin; Xu,Xiaobing; Wu,Xiaowei; Guo,Meixia; Wang,Fangyu

doi:10.3892/etm.2018.6433

Effect of JAK2/STAT3 signaling pathway on liver injury associated with severe acute pancreatitis in rats

Authors:
- Minli Li
- Xiaohua Zhang
- Bin Wang
- Xiaobing Xu
- Xiaowei Wu
- Meixia Guo
- Fangyu Wang
View Affiliations

Affiliations: Department of Gastroenterology, Nanjing Medical University, Jinling Hospital, Nanjing, Jiangsu 210002, P.R. China
Published online on: July 9, 2018 https://doi.org/10.3892/etm.2018.6433
Pages: 2013-2021
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling constitutes one of the major pathways for cytokine signal transduction. However, the role of the JAK2/STAT3 pathway in liver injury during severe acute pancreatitis (SAP) remains unclear. The aim of this study was to investigate the role of the JAK2/STAT3 signaling pathway in liver injury after SAP. In the present study 64 male Sprague‑Dawley rats were randomly divided into four groups: Control, AG490 (inhibition of JAK2), SAP and SAP with AG490. SAP was induced by retrograde infusion of 4% sodium taurocholate into the biliopancreatic duct. The activities of amylase (AMY) and liver enzymes were measured in serum. Livers and pancreas were isolated for measurements of histological damage. Blood and liver samples were taken for the measurement of TNF‑α, IL‑6 and IL‑18 concentrations. The expression levels of JAK2 and STAT3 in liver tissue were detected by immunohistochemical staining and western blotting. The results demonstrated that amylase and liver enzymes were higher in the SAP groups compared with the control, AG490 and AG490‑treated groups. The serum levels of TNF‑α, IL‑6 and IL‑18 were effectively increased in the SAP groups, whereas they were reduced by AG490. Interestingly, JAK2 and STAT3 protein expression levels were significantly increased following induction of SAP and were significantly decreased in the AG490‑pretreated groups. Administration of AG490 decreased the activity of pro‑inflammatory cytokines and significantly attenuated SAP associated‑liver injury in the rats. These results suggested that the mechanism may relate to the inhibition of TNF‑α, IL‑6 and IL‑18, and inhibiting excessive JAK2 and STAT3 activation, and may play a crucial role in the liver injury associated with SAP.

View Figures

View References

1	Shen HN, Lu CL and Li CY: Effect of diabetes on severity and hospital mortality in patients with acute pancreatitis: A national population-based study. Diabetes Care. 35:1061–1066. 2012. View Article : Google Scholar : PubMed/NCBI
2	Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, Tsiotos GG and Vege SS: Acute Pancreatitis Classification Working Group: Classification of acute pancreatitis 2012: Revision of the atlanta classification and definitions by international consensus. Gut. 62:102–111. 2013. View Article : Google Scholar : PubMed/NCBI
3	Liu Y, Liao R, Qiang Z and Zhang C: Pro-inflammatory cytokine-driven PI3K/Akt/Sp1 signalling and H₂S production facilitates the pathogenesis of severe acute pancreatitis. Biosci Rep. 37:BSR201604832017. View Article : Google Scholar : PubMed/NCBI
4	Yang J, Gallagher SF, Haines K, Epling-Burnette PK, Bai F, Gower WR Jr, Mastorides S, Norman JG and Murr MM: Kupffer cell-derived Fas ligand plays a role in liver injury and hepatocyte death. J Gastrointest Surg. 8:166–174. 2004. View Article : Google Scholar : PubMed/NCBI
5	Ou ZB, Miao CM, Ye MX, Xing DP, He K, Li PZ, Zhu RT and Gong JP: Investigation for role of tissue factor and blood coagulation system in severe acute pancreatitis and associated liver injury. Biomed Pharmacother. 85:380–388. 2017. View Article : Google Scholar : PubMed/NCBI
6	Yang J, Fier A, Carter Y, Liu G, Epling-Burnette PK, Bai F, Loughran TP Jr, Mastorides S, Norman JG and Murr MM: Liver injury during acute pancreatitis: The role of pancreatitis-associated ascitic fluid (PAAF), p38-MAPK, and caspase-3 in inducing hepatocyte apoptosis. J Gastrointest Surg. 7:200–208. 2003. View Article : Google Scholar : PubMed/NCBI
7	Folch-Puy E: Importance of the liver in systemic complications associated with acute pancreatitis: The role of Kupffer cells. J Pathol. 211:383–388. 2007. View Article : Google Scholar : PubMed/NCBI
8	O'Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB and Laurence A: The JAK-STAT pathway: Impact on human disease and therapeutic intervention. Annu Rev Med. 66:311–328. 2015. View Article : Google Scholar : PubMed/NCBI
9	Roskoski R Jr: Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases. Pharmacol Res. 111:784–803. 2016. View Article : Google Scholar : PubMed/NCBI
10	Sakamori R, Takehara T, Ohnishi C, Tatsumi T, Ohkawa K, Takeda K, Akira S and Hayashi N: Signal transducer and activator of transcription 3 signaling within hepatocytes attenuates systemic inflammatory response and lethality in septic mice. Hepatology. 46:1564–1573. 2007. View Article : Google Scholar : PubMed/NCBI
11	Aho HJ, Koskensalo SM and Nevalainen TJ: Experimental pancreatitis in the rat. Sodium taurocholate-induced acute haemorrhagic pancreatitis. Scand J Gastroenterol. 15:411–416. 1980. View Article : Google Scholar : PubMed/NCBI
12	Schmidt J, Rattner DW, Lewandrowski K, Compton CC, Mandavilli U, Knoefel WT and Warshaw AL: A better model of acute pancreatitis for evaluating therapy. Ann Surg. 215:44–56. 1992. View Article : Google Scholar : PubMed/NCBI
13	Camargo CA Jr, Madden JF, Gao W, Selvan RS and Clavien A: Interleukin-6 protects liver against warm ischemia/reperfusion injury and promotes hepatocyte proliferation in the rodent. Hepatology. 26:1513–1520. 1997. View Article : Google Scholar : PubMed/NCBI
14	Kempuraj D, Twait EC, Williard DE, Yuan Z, Meyerholz DK and Samuel I: The novel cytokine interleukin-33 activates acinar cell proinflammatory pathways and induces acute pancreatic inflammation in mice. PLoS One. 8:e568662013. View Article : Google Scholar : PubMed/NCBI
15	Geisler F, Algül H, Riemann M and Schmid RM: Questioning current concepts in acute pancreatitis: Endotoxin contamination of porcine pancreatic elastase is responsible for experimental pancreatitis-associated distant organ failure. J Immunol. 174:6431–6439. 2005. View Article : Google Scholar : PubMed/NCBI
16	Jiang Y, An Y, Jiang D, Wu B, Yang Y and Sun D: TNF-α regulating interleukin-33 induces acute pancreatic inflammation in rats. Ann Clin Lab Sci. 46:54–59. 2016.PubMed/NCBI
17	Martin MA, Saracibar E, Santamaria A, Arranz E, Garrote JA, Almaraz A, del Olmo ML, García-Pajares F, Fernández-Orcajo P, Velicia R, et al: Interleukin 18 (IL-18) and other immunological parameters as markers of severity in acute pancreatitis. Rev Esp Enferm Dig. 100:768–773. 2008.(In Spanish). PubMed/NCBI
18	Zhang XH, Li ML, Wang B, Guo MX and Zhu RM: Caspase-1 inhibition alleviates acute renal injury in rats with severe acute pancreatitis. World J Gastroenterol. 20:10457–10463. 2014. View Article : Google Scholar : PubMed/NCBI
19	Wenhong D, Jia Y, Weixing W, Xiaoyan C, Chen C, Sheng X and Hao J: Zerumbone attenuates the severity of acute necrotizing pancreatitis and pancreatitis-induced hepatic injury. Mediators Inflamm. 2012:1565072012. View Article : Google Scholar : PubMed/NCBI
20	Yang J, Gallagher SF, Haines K, Epling-Burnette PK, Bai F, Gower WR Jr, Mastorides S, Norman JG and Murr MM: Kupffer cell-derived Fas ligand plays a role in liver injury and hepatocyte death. J Gastrointest Surg. 8:166–174. 2004. View Article : Google Scholar : PubMed/NCBI
21	Chen P, Huang L, Zhang Y, Qiao M, Yao W and Yuan Y: The antagonist of the JAK-1/STAT-1 signaling pathway improves the severity of cerulein-stimulated pancreatic injury via inhibition of NF-κB activity. Int J Mol Med. 27:731–738. 2011.PubMed/NCBI
22	Damm J, Harden L, Gerstberger R, Roth J and Rummel C: The putative JAK-STAT inhibitor AG490 exacerbates LPS-fever, reduces sickness behavior, and alters the expression of pro- and anti-inflammatory genes in the rat brain. Neuropharmacology. 71:98–111. 2013. View Article : Google Scholar : PubMed/NCBI
23	Yu JH and Kim H: Role of janus kinase/signal transducers and activators of transcription in the pathogenesis of pancreatitis and pancreatic cancer. Gut Liver. 6:417–422. 2012. View Article : Google Scholar : PubMed/NCBI
24	Huang C, Ma R, Sun S, Wei G, Fang Y, Liu R and Li G: JAK2-STAT3 signaling pathway mediates thrombin-induced proinflammatory actions of microglia in vitro. J Neuroimmunol. 204:118–125. 2008. View Article : Google Scholar : PubMed/NCBI
25	Agrawal S, Gollapudi S, Su H and Gupta S: Leptin activates human B cells to secrete TNF-α, IL-6, and IL-10 via JAK2/STAT3 and p38MAPK/ERK1/2 signaling pathway. J Clin Immunol. 31:472–478. 2011. View Article : Google Scholar : PubMed/NCBI
26	Huang LY, Chen P, Xu LX, Zhou YF, Zhang YP and Yuan YZ: Fractalkine upregulates inflammation through CX3CR1 and the Jak-Stat pathway in severe acute pancreatitis rat model. Inflammation. 35:1023–1030. 2012. View Article : Google Scholar : PubMed/NCBI
27	Gallmeier E, Schäfer C, Moubarak P, Tietz A, Plössl I, Huss R, Göke B and Wagner AC: JAK and STAT proteins are expressed and activated by IFN-gamma in rat pancreatic acinar cells. J Cell Physiol. 203:209–216. 2005. View Article : Google Scholar : PubMed/NCBI
28	Wu L, Li H, Zheng SZ, Liu X, Cai H and Cai BC: Da-Huang-Fu-Zi-Tang attenuates liver injury in rats with severe acute pancreatitis. J Ethnopharmacol. 150:960–966. 2013. View Article : Google Scholar : PubMed/NCBI
29	Yu JH, Kim KH and Kim H: SOCS 3 and PPAR-gamma ligands inhibit the expression of IL-6 and TGF-beta1 by regulating JAK2/STAT3 signaling in pancreas. Int J Biochem Cell Biol. 40:677–688. 2008. View Article : Google Scholar : PubMed/NCBI
30	Robinson K, Vona-Davis L, Riggs D, Jackson B and McFadden D: Peptide YY attenuates STAT1 and STAT3 activation induced by TNF-alpha in acinar cell line AR42J. J Am Coll Surg. 202:788–796. 2006. View Article : Google Scholar : PubMed/NCBI
31	Yu JH, Kim KH and Kim H: Suppression of IL-1beta expression by the Jak 2 inhibitor AG490 in cerulein-stimulated pancreatic acinar cells. Biochem Pharmacol. 72:1555–1562. 2006. View Article : Google Scholar : PubMed/NCBI
32	Surbatovic M and Radakovic S: Tumor necrosis factor-α levels early in severe acute pancreatitis: Is there predictive value regarding severity and outcome? J Clin Gastroenterol. 47:637–643. 2013. View Article : Google Scholar : PubMed/NCBI
33	Gallagher SF, Peng Y, Haines K, Baksh K, Epling-Burnette PK, Yang J and Murr MM: Fas/FasL play a central role in pancreatitis-induced hepatocyte apoptotis. J Gastrointest Surg. 9:467–475. 2005. View Article : Google Scholar : PubMed/NCBI
34	McCormack D, McDonald D and McFadden D: Pterostilbene ameliorates tumor necrosis factor alpha-induced pancreatitis in vitro. J Surg Res. 178:28–32. 2012. View Article : Google Scholar : PubMed/NCBI
35	Ueda T, Takeyama Y, Yasuda T, Matsumura N, Sawa H, Nakajima T, Ajiki T, Fujino Y, Suzuki Y and Kuroda Y: Significant elevation of serum interleukin-18 levels in patients with acute pancreatitis. J Gastroenterol. 41:158–165. 2006. View Article : Google Scholar : PubMed/NCBI
36	Ning JW, Zhang Y, Yu MS, Gu ML, Xu J, Usman A and Ji F: Emodin alleviates intestinal mucosal injury in rats with severe acute pancreatitis via the caspase-1 inhibition. Hepatobiliary Pancreat Dis Int. 16:431–436. 2017. View Article : Google Scholar : PubMed/NCBI
37	Segersvärd R, Tsai JA, Herrington MK and Wang F: Obesity alters cytokine gene expression and promotes liver injury in rats with acute pancreatitis. Obesity (Silver Spring). 16:23–28. 2008. View Article : Google Scholar : PubMed/NCBI
38	Lv P, Fan LJ, Li HY, Meng QS and Liu J: Protective effect of thalidomide on liver injury in rats with acute pancreatitis via inhibition of oxidative stress. Ann Clin Lab Sci. 45:508–514. 2015.PubMed/NCBI