Resistin aggravates the expression of proinflammatory cytokines in cerulein‑stimulated AR42J pancreatic acinar cells

Jiang,Chong‑Yi; Wang,Wei

doi:10.3892/mmr.2016.6027

Resistin aggravates the expression of proinflammatory cytokines in cerulein‑stimulated AR42J pancreatic acinar cells

Authors:
- Chong‑Yi Jiang
- Wei Wang
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Affiliations: Department of Surgery, Huadong Hospital, Fudan University, Shanghai 200040, P.R. China
Published online on: December 12, 2016 https://doi.org/10.3892/mmr.2016.6027
Pages: 502-506

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Abstract

Resistin, an adipocytokine secreted by fat tissues, has been shown to be associated with increased local and systemic complications in acute pancreatitis (AP). However, the mechanism underlying the effect of resistin in the aggravation of AP remains to be elucidated. The aim of the present study was to investigate the functional consequences of exposing rat pancreatic acinar cells to resistin and to determine whether it amplifies proinflammatory signaling in an in vitro AP model. AR42J cells pretreated with recombinant resistin were activated by cerulein as an in vitro model of AP. The secretion of amylase was measured to evaluate the cytotoxic effect. The mRNA expression levels of tumor necrosis factor (TNF)‑α and interleukin (IL)‑6 were determined using reverse transcription‑quantitative polymerase chain reaction analysis. The nuclear protein expression levels of the nuclear factor (NF)‑κB p65 subunit were determined using western blot analysis. Resistin treatment significantly increased the secretion of amylase, and the mRNA expression levels of TNF‑α and IL‑6 in the cerulein‑induced in vitro AP model. High protein levels of the NF‑κB p65 subunit were observed in the nuclei of cells in the resistin‑treated AP model, compared with the untreated AP model. Pretreatment of the in vitro resistin‑treated AP model with the NF‑κB inhibitor, pyrrolidine dithiocarbamate decreased the protein expression of the NF‑κB p65 subunit in nuclei, and significantly attenuated the increased mRNA expression levels of TNF‑α and IL‑6 induced by resistin. The results of the present study showed that resistin increased the production of the TNF‑α and IL‑6 proinflammatory cytokines via the NF‑κB‑dependent pathway during AP. Thus, the overproduction of obesity‑associated resistin and the associated amplification of the inflammatory response may result in the aggravation of AP severity.

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1	Ogden CL, Carroll MD, Kit BK and Flegal KM: Prevalence of childhood and adult obesity in the United States, 2011–2012. Jama. 311:806–814. 2014. View Article : Google Scholar : PubMed/NCBI
2	Abu Hilal M and Armstrong T: The impact of obesity on the course and outcome of acute pancreatitis. Obes Surg. 18:326–328. 2008. View Article : Google Scholar : PubMed/NCBI
3	Chen SM, Xiong GS and Wu SM: Is obesity an indicator of complications and mortality in acute pancreatitis? An updated meta-analysis. J Dig Dis. 13:244–251. 2012. View Article : Google Scholar : PubMed/NCBI
4	Sadr-Azodi O, Orsini N, Andrén-Sandberg A and Wolk A: Abdominal and total adiposity and the risk of acute pancreatitis: A population-based prospective cohort study. Am J Gastroenterol. 108:133–139. 2013. View Article : Google Scholar : PubMed/NCBI
5	Premkumar R, Phillips AR, Petrov MS and Windsor JA: The clinical relevance of obesity in acute pancreatitis: Targeted systematic reviews. Pancreatology. 15:25–33. 2015. View Article : Google Scholar : PubMed/NCBI
6	Acharya C, Navina S and Singh VP: Role of pancreatic fat in the outcomes of pancreatitis. Pancreatology. 14:403–408. 2014. View Article : Google Scholar : PubMed/NCBI
7	Martínez J, Johnson CD, Sánchez-Paya J, de Madaria E, Robles-Diaz G and Perez-Mateo M: Obesity is a definitive risk factor of severity and mortality in acute pancreatitis: An updated meta-analysis. Pancreatology. 6:206–209. 2006. View Article : Google Scholar : PubMed/NCBI
8	Hong S, Qiwen B, Ying J, Wei A and Chaoyang T: Body mass index and the risk and prognosis of acute pancreatitis: A meta-analysis. Eur J Gastroenterol Hepatol. 23:1136–1143. 2011. View Article : Google Scholar : PubMed/NCBI
9	Johnson CD, Toh SK and Campbell MJ: Combination of APACHE-II score and an obesity score (APACHE-O) for the prediction of severe acute pancreatitis. Pancreatology. 4:1–6. 2004. View Article : Google Scholar : PubMed/NCBI
10	Grundy SM: Adipose tissue and metabolic syndrome: too much, too little or neither. Eur J Clin Invest. 45:1209–1217. 2015. View Article : Google Scholar : PubMed/NCBI
11	Vazquez-Vela ME, Torres N and Tovar AR: White adipose tissue as endocrine organ and its role in obesity. Arch Med Res. 39:715–728. 2008. View Article : Google Scholar : PubMed/NCBI
12	Cao H: Adipocytokines in obesity and metabolic disease. J Endocrinol. 220:T47–T59. 2014. View Article : Google Scholar : PubMed/NCBI
13	Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS and Lazar MA: The hormone resistin links obesity to diabetes. Nature. 409:307–312. 2001. View Article : Google Scholar : PubMed/NCBI
14	Bokarewa M, Nagaev I, Dahlberg L, Smith U and Tarkowski A: Resistin, an adipokine with potent proinflammatory properties. J Immunol. 174:5789–5795. 2005. View Article : Google Scholar : PubMed/NCBI
15	Qatanani M, Szwergold NR, Greaves DR, Ahima RS and Lazar MA: Macrophage-derived human resistin exacerbates adipose tissue inflammation and insulin resistance in mice. J Clin Invest. 119:531–539. 2009. View Article : Google Scholar : PubMed/NCBI
16	Jamaluddin MS, Weakley SM, Yao Q and Chen C: Resistin: functional roles and therapeutic considerations for cardiovascular disease. Br J Pharmacol. 165:622–632. 2012. View Article : Google Scholar : PubMed/NCBI
17	Daniel P, Leśniowski B, Jasińska A, Pietruczuk M and Malecka-Panas E: Usefulness of assessing circulating levels of resistin, ghrelin, and IL-18 in alcoholic acute pancreatitis. Dig Dis Sci. 55:2982–2987. 2010. View Article : Google Scholar : PubMed/NCBI
18	Daniel P, Leśniowski B, Mokrowiecka A, Jasińska A, Pietruczuk M and Małecka-Panas E: Circulating levels of visfatin, resistin and pro-inflammatory cytokine interleukin-8 in acute pancreatitis. Pancreatology. 10:477–482. 2010. View Article : Google Scholar : PubMed/NCBI
19	Schäffler A, Hamer O, Dickopf J, Goetz A, Landfried K, Voelk M, Herfarth H, Kopp A, Büchler C, Schölmerich J and Brünnler T: Admission resistin levels predict peripancreatic necrosis and clinical severity in acute pancreatitis. Am J Gastroenterol. 105:2474–2484. 2010. View Article : Google Scholar : PubMed/NCBI
20	Filková M, Haluzik M, Gay S and Senolt L: The role of resistin as a regulator of inflammation: Implications for various human pathologies. Clin Immunol. 133:157–170. 2009. View Article : Google Scholar : PubMed/NCBI
21	Jiang CY, Wang W, Tang JX and Yuan ZR: The adipocytokine resistin stimulates the production of proinflammatory cytokines TNF-alpha and IL-6 in pancreatic acinar cells via NF-kappaB activation. J Endocrinol Invest. 36:986–992. 2013.PubMed/NCBI
22	Song YZ, Guan J, Wang HJ, Ma W, Li F, Xu F, Ding LB, Xie L, Liu B, Liu K and Lv Z: Possible involvement of serum and synovial fluid resistin in knee osteoarthritis: Cartilage damage, clinical, and radiological links. J Clin Lab Anal. 30:437–443. 2016. View Article : Google Scholar : PubMed/NCBI
23	Barnes PJ and Karin M: Nuclear factor-kappaB: A pivotal transcription factor in chronic inflammatory diseases. N Engl J Med. 336:1066–1071. 1997. View Article : Google Scholar : PubMed/NCBI
24	Gukovsky I, Li N, Todoric J, Gukovskaya A and Karin M: Inflammation, autophagy, and obesity: Common features in the pathogenesis of pancreatitis and pancreatic cancer. Gastroenterology. 144:1199–1209, e1194. 2013. View Article : Google Scholar : PubMed/NCBI
25	Schreck RMB, Männel DN, Dröge W and Baeuerle PA: Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells. J Exp Med. 175:1181–1194. 1992. View Article : Google Scholar : PubMed/NCBI
26	Jiang ZY, Jiang CY, Wang L, Wang JC, Zhang SD, Einarsson C, Eriksson M, Han TQ, Parini P and Eggertsen G: Increased NPC1L1 and ACAT2 expression in the jejunal mucosa from Chinese gallstone patients. Biochem Biophy Res Com. 379:49–54. 2009. View Article : Google Scholar
27	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
28	Logsdon CD, Guthrie J, Alves F and Rosewicz S: Glucocorticoids have opposite effects on ornithine decarboxylase and cell growth in pancreatic acinar AR42J cells. Yale J Biol Med. 65:449–456, 465-449. 1992.PubMed/NCBI
29	Gonzalez A, Santofimia-Castaño P and Salido GM: Culture of pancreatic AR42J cell for use as a model for acinar cell function. Pancreapedia: Exocrine Pancreas Knowledge Base; 2011
30	Masamune A, Sakai Y, Satoh A, Fujita M, Yoshida M and Shimosegawa T: Lysophosphatidylcholine induces apoptosis in AR42J cells. Pancreas. 22:75–83. 2001. View Article : Google Scholar : PubMed/NCBI
31	Ye H, Zhang HJ, Xu A and Hoo RL: Resistin production from adipose tissue is decreased in db/db obese mice and is reversed by rosiglitazone. PLoS one. 8:e655432013. View Article : Google Scholar : PubMed/NCBI
32	Elsayed EY, Mosalam NA and Mohamed NR: Resistin and insulin resistance: A link between inflammation and hepatocarcinogenesis. Asian Pac J Cancer Prev. 16:7139–7142. 2015. View Article : Google Scholar : PubMed/NCBI
33	Al-Daghri N, Chetty R, McTernan PG, Al-Rubean K, Al-Attas O, Jones AF and Kumar S: Serum resistin is associated with C-reactive protein & LDL cholesterol in type 2 diabetes and coronary artery disease in a Saudi population. Cardiovasc Diabetol. 4:102005. View Article : Google Scholar : PubMed/NCBI
34	Al Hannan F and Culligan KG: Human resistin and the RELM of Inflammation in diabesity. Diabetol Metab Syndr. 7:542015. View Article : Google Scholar : PubMed/NCBI
35	Silswal N, Singh AK, Aruna B, Mukhopadhyay S, Ghosh S and Ehtesham NZ: Human resistin stimulates the pro-inflammatory cytokines TNF-alpha and IL-12 in macrophages by NF-kappaB-dependent pathway. Biochem Biophys Res Commun. 334:1092–1101. 2005. View Article : Google Scholar : PubMed/NCBI
36	Bertolani C, Sancho-Bru P, Failli P, Bataller R, Aleffi S, DeFranco R, Mazzinghi B, Romagnani P, Milani S, Ginés P, et al: Resistin as an intrahepatic cytokine: Overexpression during chronic injury and induction of proinflammatory actions in hepatic stellate cells. Am J Pathol. 169:2042–2053. 2006. View Article : Google Scholar : PubMed/NCBI
37	Cohen MC and Cohen S: Cytokine function: A study in biologic diversity. Am J Clin Pathol. 105:589–598. 1996. View Article : Google Scholar : PubMed/NCBI
38	Bhatia M: Inflammatory response on the pancreatic acinar cell injury. Scand J Surg. 94:97–102. 2005.PubMed/NCBI
39	Sunden-Cullberg J, Nyström T, Lee ML, Mullins GE, Tokics L, Andersson J, Norrby-Teglund A and Treutiger CJ: Pronounced elevation of resistin correlates with severity of disease in severe sepsis and septic shock. Crit Care Med. 35:1536–1542. 2007. View Article : Google Scholar : PubMed/NCBI
40	Suzuki S, Miyasaka K, Jimi A and Funakoshi A: Induction of acute pancreatitis by cerulein in human IL-6 gene transgenic mice. Pancreas. 21:86–92. 2000. View Article : Google Scholar : PubMed/NCBI
41	Rakonczay Z Jr, Hegyi P, Takács T, McCarroll J and Saluja AK: The role of NF-kappaB activation in the pathogenesis of acute pancreatitis. Gut. 57:259–267. 2008. View Article : Google Scholar : PubMed/NCBI
42	Chen X, Ji B, Han B, Ernst SA, Simeone D and Logsdon CD: NF-kappaB activation in pancreas induces pancreatic and systemic inflammatory response. Gastroenterology. 122:448–457. 2002. View Article : Google Scholar : PubMed/NCBI