Top

Published in:

01-05-2015 | Original Contribution

Interleukin-27, a novel cytokine induced by ischemia–reperfusion injury in rat hearts, mediates cardioprotective effects via the gp130/STAT3 pathway

Authors: Ming-Chieh Ma, Bao-Wei Wang, Tzu-Pei Yeh, Jia-Long Wu, Tun-Hui Chung, Kochung Tsui, Chih-Fan Chiang, Ai-Ju Huang, Yu-Tzu Huang

Published in: Basic Research in Cardiology | Issue 3/2015

Abstract

Patients with coronary artery disease show high serum levels of interleukin (IL)-27, a novel member of the IL-6 family. However, the function of IL-27 in hearts suffering ischemia/reperfusion (IR) injury is unclear. Here, we showed increased expression of mRNA for the IL-27 subunits, EBI3 and p28, in rat hearts after 40 min of coronary ligation and release for 7 days. This increase was associated with a peak in the release of the cardiac enzyme, creatine kinase-MB, on day 2 post-release. Moreover, levels of IL-27 receptor subunit gp130 mRNA, but not those of subunit WSX-1 mRNA, decreased in post-ischemic hearts. These results suggest that increased IL-27 production may compensate for receptor downregulation during myocardial recovery. Lactate dehydrogenase release and crystal violet staining revealed that IL-27 or IL-6 significantly attenuated severe hypoxia (SH, 2 % O₂)-induced cell damage in H9c2 cardiomyoblasts and primary rat neonatal cardiomyocytes. Incubating cardiomyocytes with IL-27 or IL-6 resulted in time-dependent activation of signal transducers and activators of transcription 3 (STAT3). Interestingly, IL-27-induced STAT3 activation was attenuated by pre-treatment with a gp130-neutralizing antibody. Blocking gp130 also reduced the cytoprotective effects of IL-27 or IL-6. Moreover, IL-27-mediated protection against SH was blocked by stattic, a small-molecule inhibitor of STAT3. IL-27 markedly improved post-ischemic recovery and reduced tissue damage in isolated perfused hearts when administered 5 min before reperfusion. These results indicate that IL-27 protects the myocardium against IR injury and facilitates the recovery of damaged cardiomyocytes via the gp130/STAT3 pathway.

Boengler K, Buechert A, Heinen Y, Roeskes C, Hilfiker-Kleiner D, Heusch G, Schulz R (2008) Cardioprotection by ischemic postconditioning is lost in aged and STAT3-deficient mice. Circ Res 102:131–135. doi:10.1161/CIRCRESAHA.107.164699 CrossRefPubMed

Boengler K, Hilfiker-Kleiner D, Drexler H, Heusch G, Schulz R (2008) The myocardial JAK/STAT pathway: from protection to failure. Pharmacol Ther 120:172–185. doi:10.1016/j.pharmthera.2008.08.002 CrossRefPubMed

Brombacher F, Kastelein RA, Alber G (2003) Novel IL-12 family members shed light on the orchestration of Th1 responses. Trends Immunol 24:207–212. doi:10.1016/S1471-4906(03)00067-X CrossRefPubMed

Chaturvedi V, Collison LW, Guy CS, Workman CJ, Vignali DA (2011) Cutting edge: human regulatory T cells require IL-35 to mediate suppression and infectious tolerance. J Immunol 186:6661–6666. doi:10.4049/jimmunol.1100315 CrossRefPubMedCentralPubMed

Chen JC, Huang AJ, Chen SC, Wu CL, Wu WM, Chiang HS, Chan CH, Lin CM, Huang YT (2012) Interleukin-27 and interleukin-12 augment activation of distinct cord blood natural killer cells responses via STAT3 pathways. J Formos Med Assoc 111:275–283. doi:10.1016/j.jfma.2010.10.002 CrossRefPubMed

Cheng X, Liao YH, Ge H, Li B, Zhang J, Yuan J, Wang M, Liu Y, Guo Z, Chen J, Zhang L (2005) TH1/TH2 functional imbalance after acute myocardial infarction: coronary arterial inflammation or myocardial inflammation. J Clin Immunol 25:246–253. doi:10.1007/s10875-005-4088-0 CrossRefPubMed

Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM, Cross R, Sehy D, Blumberg RS, Vignali DA (2007) The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450:566–569. doi:10.1038/nature06306 CrossRefPubMed

Dawn B, Xuan YT, Guo Y, Rezazadeh A, Stein AB, Hunt G, Wu WJ, Tan W, Bolli R (2004) IL-6 plays an obligatory role in late preconditioning via JAK-STAT signaling and upregulation of iNOS and COX-2. Cardiovasc Res 64:61–71. doi:10.1016/j.cardiores.2004.05.011 CrossRefPubMedCentralPubMed

Demyanets S, Kaun C, Rychli K, Pfaffenberger S, Kastl SP, Hohensinner PJ, Rega G, Katsaros KM, Afonyushkin T, Bochkov VN, Paireder M, Huk I, Maurer G, Huber K, Wojta J (2011) Oncostatin M-enhanced vascular endothelial growth factor expression in human vascular smooth muscle cells involves PI3K-, p38 MAPK-, Erk1/2- and STAT1/STAT3-dependent pathways and is attenuated by interferon-gamma. Basic Res Cardiol 106:217–231. doi:10.1007/s00395-010-0141-0 CrossRefPubMed

10.

Devergne O, Coulomb-L’Hermine A, Capel F, Moussa M, Capron F (2001) Expression of Epstein-Barr virus-induced gene 3, an interleukin-12 p40-related molecule, throughout human pregnancy: involvement of syncytiotrophoblasts and extravillous trophoblasts. Am J Pathol 159:1763–1776. doi:10.1016/S0002-9440(10)63023-4 CrossRefPubMedCentralPubMed

11.

Dougall WC, Nick HS (1991) Manganese superoxide dismutase: a hepatic acute phase protein regulated by interleukin-6 and glucocorticoids. Endocrinology 129:2376–2384. doi:10.1210/endo-129-5-2376 CrossRefPubMed

12.

Frangogiannis HG, Smith CW, Entman ML (2002) The inflammatory response in myocardial infarction. Cardiovasc Res 53:31–47. doi:10.1016/S0008-6363(01)00434-5 CrossRefPubMed

13.

Fuglesteg BN, Suleman N, Tiron C, Kanhema T, Lacerda L, Andreasen TV, Sack MN, Jonassen AK, Mjos OD, Opie LH, Lecour S (2008) Signal transducer and activator of transcription 3 is involved in the cardioprotective signalling pathway activated by insulin therapy at reperfusion. Basic Res Cardiol 103:444–453. doi:10.1007/s00395-008-0728-x CrossRefPubMedCentralPubMed

14.

Heusch G, Boengler K, Schulz R (2008) Cardioprotection: nitric oxide, protein kinases, and mitochondria. Circulation 118:1915–1919. doi:10.1161/CIRCULATIONAHA.108.805242 CrossRefPubMed

15.

Heusch G, Musiolik J, Gedik N, Skyschally A (2011) Mitochondrial STAT3 activation and cardioprotection by ischemic postconditioning in pigs with regional myocardial ischemia/reperfusion. Circ Res 109:1302–1308. doi:10.1161/CIRCRESAHA.111.255604 CrossRefPubMed

16.

Hilfiker-Kleiner D, Kaminski K, Podewski E, Bonda T, Schaefer A, Sliwa K, Forster O, Quint A, Landmesser U, Doerries C, Luchtefeld M, Poli V, Schneider MD, Balligand JL, Desjardins F, Ansari A, Struman I, Nguyen NQ, Zschemisch NH, Klein G, Heusch G, Schulz R, Hilfiker A, Drexler H (2007) A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell 128:589–600. doi:10.1016/j.cell.2006.12.036 CrossRefPubMed

17.

Hirano T, Ishihara K, Hibi M (2000) Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene 19:2548–2556. doi:10.1038/sj.onc.1203551 CrossRefPubMed

18.

Hirota H, Chen J, Betz UA, Rajewsky K, Gu Y, Ross J Jr, Muller W, Chien KR (1999) Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stress. Cell 97:189–198. doi:10.1016/S0092-8674(00)80729-1 CrossRefPubMed

19.

Ihle JN (1996) STATs: signal transducers and activators of transcription. Cell 84:331–334CrossRefPubMed

20.

Jafarzadeh A, Nemati M, Rezayati MT (2011) Serum levels of interleukin (IL)-27 in patients with ischemic heart disease. Cytokine 56:153–156. doi:10.1016/j.cyto.2011.06.014 CrossRefPubMed

21.

Kaneko K, Kanda T, Yokoyama T, Nakazato Y, Iwasaki T, Kobayashi I, Nagai R (1997) Expression of interleukin-6 in the ventricles and coronary arteries of patients with myocardial infarction. Res Commun Mol Pathol Pharmacol 97:3–12PubMed

22.

Kelly RF, Lamont KT, Somers S, Hacking D, Lacerda L, Thomas P, Opie LH, Lecour S (2010) Ethanolamine is a novel STAT-3 dependent cardioprotective agent. Basic Res Cardiol 105:763–770. doi:10.1007/s00395-010-0125-0 CrossRefPubMed

23.

Kimes BW, Brandt BL (1976) Properties of a clonal muscle cell line from rat heart. Exp Cell Res 98:367–381. doi:10.1016/0014-4827(76)90447-X CrossRefPubMed

24.

Klausen TON, Poulsen TD, Richalet JP, Pedersen BK (1997) Hypoxemia increases serum interleukin-6 in humans. Eur J Appl Physiol Occup Physiol 76:480–482CrossRefPubMed

25.

Kleinbongard P, Heusch G, Schulz R (2010) TNFα in atherosclerosis, myocardial ischemia/reperfusion and heart failure. Pharmacol Ther 127:295–314. doi:10.1016/j.pharmthera.2010.05.002 CrossRefPubMed

26.

Kodama H, Fukuda K, Pan J, Makino S, Baba A, Hori S, Ogawa S (1997) Leukemia inhibitory factor, a potent cardiac hypertrophic cytokine, activates the JAK/STAT pathway in rat cardiomyocytes. Circ Res 81:656–663. doi:10.1161/01.RES.81.5.656 CrossRefPubMed

27.

Krishnamurthy P, Rajasingh J, Lambers E, Qin G, Losordo DW, Kishore R (2009) IL-10 inhibits inflammation and attenuates left ventricular remodeling after myocardial infarction via activation of STAT3 and suppression of HuR. Circ Res 104:e9–e18. doi:10.1161/CIRCRESAHA.108.188243 CrossRefPubMedCentralPubMed

28.

Lacerda L, Somers S, Opie LH, Lecour S (2009) Ischaemic postconditioning protects against reperfusion injury via the SAFE pathway. Cardiovasc Res 84:201–208. doi:10.1093/cvr/cvp274 CrossRefPubMed

29.

Lin JS, Chen YS, Chiang HS, Ma MC (2008) Hypoxic preconditioning protects rat hearts against ischaemia-reperfusion injury: role of erythropoietin on progenitor cell mobilization. J Physiol 586:5757–5769. doi:10.1113/jphysiol.2008.160887 CrossRefPubMedCentralPubMed

30.

Lu MJ, Chen YS, Huang HS, Ma MC (2014) Hypoxic preconditioning protects rat hearts against ischemia–reperfusion injury via the arachidonate12-lipoxygenase/transient receptor potential vanilloid 1 pathway. Basic Res Cardiol 109:414. doi:10.1007/s00395-014-0414-0 CrossRefPubMed

31.

Matsui H, Ihara Y, Fujio Y, Kunisada K, Akira S, Kishimoto T, Yamauchi-Takihara K (1999) Induction of interleukin (IL)-6 by hypoxia is mediated by nuclear factor (NF)-kB and NF-IL6 in cardiac myocytes. Cardiovasc Res 42:104–112. doi:10.1016/S0008-6363(98)00285-5 CrossRefPubMed

32.

Matsushita K, Oda T, Kimura K, Shimada M, Sano M, Umezawa A, Hata J, Ogawa S (2005) Interleukin-6/soluble interleukin-6 receptor complex reduces infarct size via inhibiting myocardial apoptosis. Lab Invest 85:1210–1223. doi:10.1038/labinvest.3700322 CrossRefPubMed

33.

Negoro S, Kunisada K, Fujio Y, Funamoto M, Darville MI, Eizirik DL, Osugi T, Izumi M, Oshima Y, Nakaoka Y, Hirota H, Kishimoto T, Yamauchi-Takihara K (2001) Activation of signal transducer and activator of transcription 3 protects cardiomyocytes from hypoxia/reoxygenation-induced oxidative stress through the upregulation of manganese superoxide dismutase. Circulation 104:979–981. doi:10.1161/hc3401.095947 CrossRefPubMed

34.

Pagliaro P, Penna C (2014) Redox signaling and cardioprotection—translatability and mechanism. Br J Pharmacol. doi:10.1111/bph.12975

35.

Pedretti S, Raddatz E (2011) STAT3alpha interacts with nuclear GSK3beta and cytoplasmic RISK pathway and stabilizes rhythm in the anoxic-reoxygenated embryonic heart. Basic Res Cardiol 106:355–369. doi:10.1007/s00395-011-0152-5 CrossRefPubMed

36.

Pflanz S, Hibbert L, Mattson J, Rosales R, Vaisberg E, Bazan JF, Phillips JH, McClanahan TK, de Waal Malefyt R, Kastelein RA (2004) WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27. J Immunol 172:2225–2231. doi:10.4049/jimmunol.172.4.2225 CrossRefPubMed

37.

Pflanz S, Timans JC, Cheung J, Rosales R, Kanzler H, Gilbert J, Hibbert L, Churakova T, Travis M, Vaisberg E, Blumenschein WM, Mattson JD, Wagner JL, To W, Zurawski S, McClanahan TK, Gorman DM, Bazan JF, de Waal Malefyt R, Rennick D, Kastelein RA (2002) IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4(+) T cells. Immunity 16:779–790CrossRefPubMed

38.

Railson JE, Liao Z, Brar BK, Buddle JC, Pennica D, Stephanou A, Latchman DS (2002) Cardiotrophin-1 and urocortin cause protection by the same pathway and hypertrophy via distinct pathways in cardiac myocytes. Cytokine 17:243–253. doi:10.1006/cyto.2001.1011 CrossRefPubMed

39.

Sanchez RN, Chan CK, Garg S, Kwong JM, Wong MJ, Sadun AA, Lam TT (2003) Interleukin-6 in retinal ischemia reperfusion injury in rats. Invest Ophthalmol Vis Sci 44:4006–4011. doi:10.1159/000050880 CrossRefPubMed

40.

Shyu KG, Chen CC, Wang BW, Kuan P (2001) Angiotensin II receptor antagonist blocks the expression of connexin43 induced by cyclical mechanical stretch in cultured neonatal rat cardiac myocytes. J Mol Cell Cardiol 33:691–698. doi:10.1006/jmcc.2000.1333 CrossRefPubMed

41.

Smart N, Mojet MH, Latchman DS, Marber MS, Duchen MR, Heads RJ (2006) IL-6 induces PI3-kinase and nitric oxide-dependent protection and preserves mitochondrial function in cardiomyocytes. Cardiovasc Res 69:164–177. doi:10.1016/j.cardiores.2005.08.017 CrossRefPubMed

42.

Takahashi N, Saito Y, Kuwahara K, Harada M, Tanimoto K, Nakagawa Y, Kawakami R, Nakanishi M, Yasuno S, Usami S, Yoshimura A, Nakao K (2005) Hypertrophic responses to cardiotrophin-1 are not mediated by STAT3, but via a MEK5-ERK5 pathway in cultured cardiomyocytes. J Mol Cell Cardiol 38:185–192. doi:10.1016/j.yjmcc.2004.10.016 CrossRefPubMed

43.

Tiberio L, Tiberio GA, Bardella L, Cervi E, Cerea K, Dreano M, Garotta G, Fra A, Montani N, Ferrari-Bravo A, Callea F, Grigolato P, Giulini SM, Schiaffonati L (2006) Mechanisms of interleukin-6 protection against ischemia–reperfusion injury in rat liver. Cytokine 34:131–142. doi:10.1016/j.cyto.2006.04.009 CrossRefPubMed

44.

Tsan MF, White JE, Treanor C, Shaffer JB (1990) Molecular basis for tumor necrosis factor-induced increase in pulmonary superoxide dismutase activities. Am J Physiol 259:L506–L512. doi:10.1016/S1074-7613(02)00324-2 PubMed

45.

Wegrzyn J, Potla R, Chwae YJ, Sepuri NB, Zhang Q, Koeck T, Derecka M, Szczepanek K, Szelag M, Gornicka A, Moh A, Moghaddas S, Chen Q, Bobbili S, Cichy J, Dulak J, Baker DP, Wolfman A, Stuehr D, Hassan MO, Fu XY, Avadhani N, Drake JI, Fawcett P, Lesnefsky EJ, Larner AC (2009) Function of mitochondrial Stat3 in cellular respiration. Science 323:793–797. doi:10.1126/science.1164551 CrossRefPubMedCentralPubMed

46.

Yamauchi-Takihara K, Kishimoto T (2000) Cytokines and their receptors in cardiovascular diseases–role of gp130 signalling pathway in cardiac myocyte growth and maintenance. Int J Exp Pathol 81:1–16. doi:10.1046/j.1365-2613.2000.00139.x CrossRefPubMedCentralPubMed

47.

Yan SF, Zou YS, Mendelsohn M, Gao Y, Naka Y, Du Yan S, Pinsky D, Stern D (1997) Nuclear factor interleukin 6 motifs mediate tissue-specific gene transcription in hypoxia. J Biol Chem 272:4287–4294. doi:10.1074/jbc.272.7.4287 CrossRefPubMed

48.

Yoshida H, Miyazaki Y (2008) Regulation of immune responses by interleukin-27. Immunol Rev 226:234–247. doi:10.1111/j.1600-065X.2008.00710.x CrossRefPubMed

Title: Interleukin-27, a novel cytokine induced by ischemia–reperfusion injury in rat hearts, mediates cardioprotective effects via the gp130/STAT3 pathway
Authors: Ming-Chieh Ma
Bao-Wei Wang
Tzu-Pei Yeh
Jia-Long Wu
Tun-Hui Chung
Kochung Tsui
Chih-Fan Chiang
Ai-Ju Huang
Yu-Tzu Huang
Publication date: 01-05-2015
Publisher: Springer Berlin Heidelberg
Published in: Basic Research in Cardiology / Issue 3/2015
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-015-0480-y

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Interleukin-27, a novel cytokine induced by ischemia–reperfusion injury in rat hearts, mediates cardioprotective effects via the gp130/STAT3 pathway

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2015

Cardiac myosin-binding protein C: a potential early biomarker of myocardial injury

Complement system modulation as a target for treatment of arrhythmogenic cardiomyopathy

Dickkopf-3 protects against cardiac dysfunction and ventricular remodelling following myocardial infarction

MCP-1-induced protein attenuates post-infarct cardiac remodeling and dysfunction through mitigating NF-κB activation and suppressing inflammation-associated microRNA expression

A long way to translation: will cMyC survive?

Sialyltransferase7A, a Klf4-responsive gene, promotes cardiomyocyte apoptosis during myocardial infarction

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page