Abstract
Glucocorticoids are commonly used for the treatment of pancreatitis and complicated acute lung injury and help to reduce the mortality rates of both. The effect of gene variants in heat shock protein 90 (Hsp90), a key chaperone molecule of the glucocorticoid receptor (GR), on the therapeutic effect of glucocorticoids is unclear. Our study aims to investigate the different susceptibility to glucocorticoid treatment in BALB/c and C57BL/6 mice carrying different Hsp90 genotypes in an animal model of pancreatitis-induced lung injury. Compared with BALB/c mice, C57BL/6 mice have lower mortality rates, decreased water content in their lungs, and a lower level of IL-1 beta in an animal model of acute pancreatitis. C57BL/6 mice show a greater therapeutic effect and increased GR binding activities with glucocorticoid responsive element compared to BALB/c mice after a 0.4 mg/kg dexamethasone (DEX) treatment. Treatment with a higher dose of DEX (4 mg/kg) significantly reduced mortality rates and increased GR-GRE binding activity in both strains of mice, and there was no significant difference between the two strains. DEX did not exert a protective role after geldanamycin, a specific inhibitor of Hsp90, was administered in both strains of mice. Our study revealed that Hsp90 gene variants are responsible for the greater therapeutic effect of DEX in C57BL/6 mice compared to BALB/c mice, which implies that combining DEX treatment with Hsp90 regulation would promote the efficiency of DEX and would be an effective way to alleviate the side effects of hormone therapy.
Similar content being viewed by others
References
Lerch MM, Albrecht E, Ruthenburger M, Mayerle J, Halangk W, Kruger B (2003) Pathophysiology of alcohol-induced pancreatitis. Pancreas 27:291–296
Shen HY, Zhao Y, Chen XY, Xiong RP, Lu JL, Chen JF, Chen LY, Zhou YG (2010) Differential alteration of heat shock protein 90 in mice modifies glucocorticoid receptor function and susceptibility to trauma. J Neurotrauma 27:373–381. doi:10.1089/neu.2009.0926
Nemoto T, Ohara-Nemoto Y, Ota M, Takagi T, Yokoyama K (1995) Mechanism of dimer formation of the 90-kDa heat-shock protein. Eur J Biochem 233:1–8
Jibard N, Meng X, Leclerc P, Rajkowski K, Fortin D, Schweizer-Groyer G, Catelli MG, Baulieu EE, Cadepond F (1999) Delimitation of two regions in the 90-kDa heat shock protein (Hsp90) able to interact with the glucocorticosteroid receptor (GR). Exp Cell Res 247:461–474. doi:10.1006/excr.1998.4375
Passarino G, Cavalleri GL, Stecconi R, Franceschi C, Altomare K, Dato S, Greco V, Luca Cavalli Sforza L, Underhill PA, de Benedictis G (2003) Molecular variation of human HSP90alpha and HSP90beta genes in Caucasians. Hum Mutat 21:554–555. doi:10.1002/humu.9141
MacLean MJ, Llordella MM, Bot N, Picard D (2005) A yeast-based assay reveals a functional defect of the Q488H polymorphism in human Hsp90alpha. Biochem Biophys Res Commun 337:133–137. doi:10.1016/j.bbrc.2005.09.025
Shen HY, He JC, Wang Y, Huang QY, Chen JF (2005) Geldanamycin induces heat shock protein 70 and protects against MPTP-induced dopaminergic neurotoxicity in mice. J Biol Chem 280:39962–39969. doi:10.1074/jbc.M505524200
Abe R, Shimosegawa T, Kikuchi Y, Kimura K, Nagasaki Y, Koizumi M, Toyota T (1996) The role of pituitary-adrenal counterregulation of inflammation in cerulein-induced pancreatitis: a comparison between Fischer and Lewis rats. Pancreas 12:280–285
Ulett GC, Ketheesan N, Hirst RG (2000) Cytokine gene expression in innately susceptible BALB/c mice and relatively resistant C57BL/6 mice during infection with virulent Burkholderia pseudomallei. Infect Immun 68:2034–2042
Gorelick FS (2016) Advances in pancreatology: 2016. Curr Opin Gastroenterol. doi:10.1097/MOG.0000000000000299
Malla SR, Karrman Mardh C, Gunther A, Mahajan UM, Sendler M, D’Haese J, Weiss FU, Lerch MM, Hansen MB, Mayerle J (2016) Effect of oral administration of AZD8309, a CXCR2 antagonist, on the severity of experimental pancreatitis. Pancreatology. doi:10.1016/j.pan.2016.07.005
Thrower E, Husain S, Gorelick F (2008) Molecular basis for pancreatitis. Curr Opin Gastroenterol 24:580–585. doi:10.1097/MOG.0b013e32830b10e6
Cadepond F, Jibard N, Binart N, Schweizer-Groyer G, Segard-Maurel I, Baulieu EE (1994) Selective deletions in the 90 kDa heat shock protein (hsp90) impede hetero-oligomeric complex formation with the glucocorticosteroid receptor (GR) or hormone binding by GR. J Steroid Biochem Mol Biol 48:361–367
Hurt DE, Suzuki S, Mayama T, Charmandari E, Kino T (2016) Structural analysis on the pathologic mutant glucocorticoid receptor ligand-binding domains. Mol Endocrinol 30:173–188. doi:10.1210/me.2015-1177
Cain DW, Cidlowski JA (2015) Specificity and sensitivity of glucocorticoid signaling in health and disease. Best Pract Res Clin Endocrinol Metab 29:545–556. doi:10.1016/j.beem.2015.04.007
Zhang S, Lv C, Yang X, Han Z, Zhang S, Zhang J, Zong C, Gao L, Li L, Zhao Q, Li R, Yang Y, Yu F, Li X, Zhang P, Wei L (2015) Corticosterone mediates the inhibitory effect of restraint stress on the migration of mesenchymal stem cell to carbon tetrachloride-induced fibrotic liver by downregulating CXCR4/7 expression. Stem Cells Dev 24:587–596. doi:10.1089/scd.2014.0243
Besedovsky L, Born J, Lange T (2014) Endogenous glucocorticoid receptor signaling drives rhythmic changes in human T-cell subset numbers and the expression of the chemokine receptor CXCR4. FASEB J 28:67–75. doi:10.1096/fj.13-237958
Cao MH, Xu J, Cai HD, Lv ZW, Feng YJ, Li K, Chen CQ, Li YY (2015) p38 MAPK inhibition alleviates experimental acute pancreatitis in mice. Hepatobiliary Pancreat Dis Int 14:101–106
Ramudo L, Yubero S, Manso MA, Sanchez-Recio J, Weruaga E, De Dios I (2010) Effects of dexamethasone on intercellular adhesion molecule 1 expression and inflammatory response in necrotizing acute pancreatitis in rats. Pancreas 39:1057–1063. doi:10.1097/MPA.0b013e3181da0f3e
Xu J, Huang B, Wang Y, Tong C, Xie P, Fan R, Gao Z (2016) Emodin ameliorates acute lung injury induced by severe acute pancreatitis through the up-regulated expressions of AQP1 and AQP5 in lung. Clin Exp Pharmacol Physiol 43:1071–1079. doi:10.1111/1440-1681.12627
Han X, Wang Y, Chen H, Zhang J, Xu C, Li J, Li M (2016) Enhancement of ICAM-1 via the JAK2/STAT3 signaling pathway in a rat model of severe acute pancreatitis-associated lung injury. Exp Ther Med 11:788–796. doi:10.3892/etm.2016.2988
De Bosscher K, Vanden Berghe W, Haegeman G (2000) Mechanisms of anti-inflammatory action and of immunosuppression by glucocorticoids: negative interference of activated glucocorticoid receptor with transcription factors. J Neuroimmunol 109:16–22
Abe R, Shimosegawa T, Kimura K, Abe T, Kashimura J, Koizumi M, Toyota T (1995) The role of endogenous glucocorticoids in rat experimental models of acute pancreatitis. Gastroenterology 109:933–943
Li YY, Ochs S, Gao ZR, Malo A, Chen CJ, Lv S, Gallmeier E, Goke B, Schafer C (2009) Regulation of HSP60 and the role of MK2 in a new model of severe experimental pancreatitis. Am J Physiol Gastrointest Liver Physiol 297:G981–G989
Lee J, Seo JH, Lim JW, Kim H (2010) Membrane proteome analysis of cerulein-stimulated pancreatic acinar cells: implication for early event of acute pancreatitis. Gut Liver 4:84–93. doi:10.5009/gnl.2010.4.1.84
Li YY, Li XJ, Lv S, Li K, Li YN, Gao ZR, Feng JY, Chen CJ, Schaefer C (2010) Ascitic fluid and serum from rats with acute pancreatitis injure rat pancreatic tissues and alter the expression of heat shock protein 60. Cell Stress Chaperones 15:583–591. doi:10.1007/s12192-010-0170-5
Ye R, Mareninova OA, Barron E, Wang M, Hinton DR, Pandol SJ, Lee AS (2010) Grp78 heterozygosity regulates chaperone balance in exocrine pancreas with differential response to cerulein-induced acute pancreatitis. Am J Pathol 177:2827–2836. doi:10.2353/ajpath.2010.100368
Liu Y, Zhou ZG, Chen KL, Zhou B, Yang L, Yan H, Li Y (2012) The ER chaperone GRP78 is associated with the severity of cerulein-induced pancreatic inflammation via regulating apoptosis of pancreatic acinar cells. Hepatogastroenterology 59:1670–1676. doi:10.5754/hge12281
Kim JN, Lee HS, Ryu SH, Kim YS, Moon JS, Kim CD, Chang IY, Yoon SP (2011) Heat shock proteins and autophagy in rats with cerulein-induced acute pancreatitis. Gut Liver 5:513–520. doi:10.5009/gnl.2011.5.4.513
Feng JY, Li YY (2010) Alteration and role of heat shock proteins in acute pancreatitis. J Dig Dis 11:277–283. doi:10.1111/j.1751-2980.2010.00450.x
Moretti AI, Rios EC, Soriano FG, de Souza HP, Abatepaulo F, Barbeiro DF, Velasco IT (2009) Acute pancreatitis: hypertonic saline increases heat shock proteins 70 and 90 and reduces neutrophil infiltration in lung injury. Pancreas 38:507–514. doi:10.1097/MPA.0b013e31819fef75
Meng K, Liu Q, Dou Y, Huang Q (2013) Prior peritoneal lavage with hot 0.9% saline induces HSP70 expression and protects against cerulein-induced acute pancreatitis in rats. Mol Biol Rep 40:1443–1449. doi:10.1007/s11033-012-2187-6
Nakada S, Tsuneyama K, Kato I, Tabuchi Y, Takasaki I, Furusawa Y, Kawaguchi H, Fujimoto M, Goto H, Hikiami H, Kondo T, Takano Y, Shimada Y (2010) Identification of candidate genes involved in endogenous protection mechanisms against acute pancreatitis in mice. Biochem Biophys Res Commun 391:1342–1347. doi:10.1016/j.bbrc.2009.12.047
Szabolcs A, Biczo G, Rakonczay Z, Tiszlavicz L, Halm G, Wittmann T, Takacs T (2009) Simultaneous proteosome inhibition and heat shock protein induction by bortezomib is beneficial in experimental pancreatitis. Eur J Pharmacol 616:270–274. doi:10.1016/j.ejphar.2009.05.019
Lunova M, Zizer E, Kucukoglu O, Schwarz C, Dillmann WH, Wagner M, Strnad P (2012) Hsp72 overexpression accelerates the recovery from caerulein-induced pancreatitis. PLoS ONE 7:e39972. doi:10.1371/journal.pone.0039972
Bamberger CM, Wald M, Bamberger AM, Schulte HM (1997) Inhibition of mineralocorticoid and glucocorticoid receptor function by the heat shock protein 90-binding agent geldanamycin. Mol Cell Endocrinol 131:233–240
Zhao Y, Shen HY, Chen XY, Xiong RP, Li P, Liu P, Yang N, Zhou YG (2010) Genetic variations of heat shock protein 84 in mice mediate cellular glucocorticoid response. Cell Physiol Biochem 25:359–366. doi:10.1159/000303039
Acknowledgements
This work was supported by the National Natural Science Foundation of China [Grant 30470988] and the Foundation for the Author of National Excellent Doctoral Dissertation of China [Grant 200156].
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors have declared that no conflict of interest exists.
Rights and permissions
About this article
Cite this article
Zhao, Y., Xiong, RP., Chen, X. et al. Hsp90 regulation affects the treatment of glucocorticoid for pancreatitis-induced lung injury. Mol Cell Biochem 440, 189–197 (2018). https://doi.org/10.1007/s11010-017-3166-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11010-017-3166-y