Neuroprotective effect of interleukin-6 in a rat model of cerebral ischemia

Feng,Qilin; Wang,Yi; Yang,Yingda

doi:10.3892/etm.2015.2363

Neuroprotective effect of interleukin-6 in a rat model of cerebral ischemia

Authors:
- Qilin Feng
- Yi Wang
- Yingda Yang
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Affiliations: Department of Pharmacy, Central Hospital of Wuhan, Wuhan, Hubei 430030, P.R. China, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
Published online on: March 16, 2015 https://doi.org/10.3892/etm.2015.2363
Pages: 1695-1701
Copyright: © Feng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Interleukin (IL)-6 is known to be a key cytokine in immune regulation in addition to serving crucial functions in various autoimmune diseases; however, the neuroprotective potential of IL‑6 has not been fully investigated. The aim of the present study was to investigate the neuroprotective effects of the inflammatory cytokine IL‑6 in a rat model of cerebral ischemia. Rat cerebral ischemia was induced by intraluminal middle cerebral artery occlusion. Following treatment with 500 or 50 ng IL‑6, the infarct volumes and symptoms of neurological deficit were ameliorated. Furthermore, terminal deoxynucleotidyl transferase‑mediated dUTP nick end labeling staining suggested that the IL‑6 treatment reduced neuronal apoptosis in vivo, which was consistent with a lower percentage of annexin V- and caspase‑3‑positive cortical neurons. In addition, IL‑6 in vitro induced the phosphorylation of signal transducer and activator of transcription (STAT) 3 and the expression of induced myeloid leukemia cell differentiation protein Mcl‑1, but not the expression of B‑cell lymphoma 2, suggesting the activation of the Janus kinase/STAT pathway by IL‑6. IL‑6 also appeared to be involved in the regulation of cytokine secretion and blood‑brain barrier (BBB) integrity in cerebral ischemia. IL‑6 downregulated a number of inflammatory cytokines, including tumor necrosis factor‑α and IL‑1β, as well as myeloperoxidase activity, indicating the accumulation of granulocytes in the ischemic brain tissue. IL‑6 was also observed to support the integrity of the BBB by reducing Evans blue leakage in vivo and suppressing the expression of matrix metalloproteinase‑9 in ischemic brain tissue. In conclusion, the results of the present study indicate that the neuroprotective effects of IL‑6 in cerebral ischemia are the result of a range of processes, including the modulation of cell apoptosis, cytokine secretion and the integrity of the BBB. IL‑6 could therefore be used as a therapeutic agent in clinical practice.

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1	Amantea D, Nappi G, Bernardi G, Bagetta G and Corasaniti MT: Post-ischemic brain damage: Pathophysiology and role of inflammatory mediators. FEBS J. 276:13–26. 2009. View Article : Google Scholar : PubMed/NCBI
2	Wang Y, Cao M, Liu A, Di W, Zhao F, Tian Y and Jia J: Changes of inflammatory cytokines and neurotrophins emphasized their roles in hypoxic-ischemic brain damage. Int J Neurosci. 123:191–195. 2013. View Article : Google Scholar : PubMed/NCBI
3	Pradillo JM, Denes A, Greenhalgh AD, Boutin H, Drake C, McColl BW, Barton E, Proctor SD, Russell JC, Rothwell NJ and Allan SM: Delayed administration of interleukin-1 receptor antagonist reduces ischemic brain damage and inflammation in comorbid rats. J Cereb Blood Flow Metab. 32:1810–1819. 2012. View Article : Google Scholar : PubMed/NCBI
4	Kishimoto T: The biology of interleukin-6. Blood. 74:1–10. 1989.PubMed/NCBI
5	Wakabayashi K, Nagai A, Sheikh AM, Shiota Y, Narantuya D, Watanabe T, Masuda J, Kobayashi S, Kim SU and Yamaguchi S: Transplantation of human mesenchymal stem cells promotes functional improvement and increased expression of neurotrophic factors in a rat focal cerebral ischemia model. J Neurosci Res. 88:1017–1025. 2010.PubMed/NCBI
6	Nakamachi T, Tsuchida M, Kagami N, Yofu S, Wada Y, Hori M, Tsuchikawa D, Yoshikawa A, Imai N, Nakamura K, et al: IL-6 and PACAP receptor expression and localization after global brain ischemia in mice. J Mol Neurosci. 48:518–525. 2012. View Article : Google Scholar : PubMed/NCBI
7	Hama T, Kushima Y, Miyamoto M, Kubota M, Takei N and Hatanaka H: Interleukin-6 improves the survival of mesencephalic catecholaminergic and septal cholinergic neurons from postnatal, two-week-old rats in cultures. Neuroscience. 40:445–452. 1991. View Article : Google Scholar : PubMed/NCBI
8	Dooley D, Vidal P and Hendrix S: Immunopharmacological intervention for successful neural stem cell therapy: New perspectives in CNS neurogenesis and repair. Pharmacol Ther. 141:21–31. 2014. View Article : Google Scholar : PubMed/NCBI
9	Brázda V, Klusáková I, Hradilová Svíženská I and Dubový P: Dynamic response to peripheral nerve injury detected by in situ hybridization of IL-6 and its receptor mRNAs in the dorsal root ganglia is not strictly correlated with signs of neuropathic pain. Mol Pain. 9:422013. View Article : Google Scholar : PubMed/NCBI
10	Allodi I, Udina E and Navarro X: Specificity of peripheral nerve regeneration: Interactions at the axon level. Prog Neurobiol. 98:16–37. 2012. View Article : Google Scholar : PubMed/NCBI
11	Hibi M, Nakajima K and Hirano T: IL-6 cytokine family and signal transduction: A model of the cytokine system. J Mol Med Berl. 74:1–12. 1996. View Article : Google Scholar : PubMed/NCBI
12	Heim MH: The Jak-STAT pathway: Cytokine signalling from the receptor to the nucleus. J Recept Signal Transduct Res. 19:75–120. 1999. View Article : Google Scholar : PubMed/NCBI
13	Heinrich PC, Behrmann I, Müller-Newen G, Schaper F and Graeve L: Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J. 334:297–314. 1998.PubMed/NCBI
14	Adams JM and Cory S: The Bcl-2 protein family: Arbiters of cell survival. Science. 281:1322–1326. 1998. View Article : Google Scholar : PubMed/NCBI
15	Puthier D, Pellat-Deceunynck C, Barillé S, Robillard N, Rapp MJ, Juge-Morineau N, Harousseau JL, Bataille R and Amiot M: Differential expression of Bcl-2 in human plasma cell disorders according to proliferation status and malignancy. Leukemia. 13:289–294. 1999. View Article : Google Scholar : PubMed/NCBI
16	Tu Y, Renner S, Xu F, Fleishman A, Taylor J, Weisz J, Vescio R, Rettig M, Berenson J, Krajewski S, et al: BCL-X expression in multiple myeloma: Possible indicator of chemoresistance. Cancer Res. 58:256–262. 1998.PubMed/NCBI
17	Altmeyer A, Simmons RC, Krajewski S, Reed JC, Bornkamm GW and Chen-Kiang S: Reversal of EBV immortalization precedes apoptosis in IL-6-induced human B cell terminal differentiation. Immunity. 7:667–677. 1997. View Article : Google Scholar : PubMed/NCBI
18	Lømo J, Smeland EB, Krajewski S, Reed JC and Blomhoff HK: Expression of the Bcl-2 homologue Mcl-1 correlates with survival of peripheral blood B lymphocytes. Cancer Res. 56:40–43. 1996.PubMed/NCBI
19	Mérino D, Khaw SL, Glaser SP, Anderson DJ, Belmont LD, Wong C, Yue P, Robati M, Phipson B, Fairlie WD, et al: Bcl-2, Bcl-x(L), and Bcl-w are not equivalent targets of ABT-737 and navitoclax (ABT-263) in lymphoid and leukemic cells. Blood. 119:5807–5816. 2012. View Article : Google Scholar : PubMed/NCBI
20	Dimberg LY, Dimberg A, Ivarsson K, Fryknäs M, Rickardson L, Tobin G, Ekman S, Larsson R, Gullberg U, Nilsson K, et al: Stat1 activation attenuates IL-6 induced Stat3 activity but does not alter apoptosis sensitivity in multiple myeloma. BMC Cancer. 12:3182012. View Article : Google Scholar : PubMed/NCBI
21	Longa EZ, Weinstein PR, Carlson S and Cummins R: Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke. 20:84–91. 1989. View Article : Google Scholar : PubMed/NCBI
22	Matsuo Y, Onodera H, Shiga Y, Nakamura M, Ninomiya M, Kihara T and Kogure K: Correlation between myeloperoxidase-quantified neutrophil accumulation and ischemic brain injury in the rat. Effects of neutrophil depletion. Stroke. 25:1469–1475. 1994. View Article : Google Scholar : PubMed/NCBI
23	Lou HY, Zhang XM, Wei XB, Wang RX and Sun X: Anti-inflammatory effect of hydroxyethylpuerarin on focal brain ischemia/reperfusion injury in rats. Chin J Physiol. 47:197–201. 2004.PubMed/NCBI
24	Gürsoy-Ozdemir Y, Bolay H, Saribaş O and Dalkara T: Role of endothelial nitric oxide generation and peroxynitrite formation in reperfusion injury after focal cerebral ischemia. Stroke. 31:1974–1981. 2000. View Article : Google Scholar : PubMed/NCBI
25	LaFerla FM, Tinkle BT, Bieberich CJ, Haudenschild CC and Jay G: The Alzheimers A beta peptide induces neurodegeneration and apoptotic cell death in transgenic mice. Nat Genet. 9:21–30. 1995. View Article : Google Scholar : PubMed/NCBI
26	Miravalle L, Tokuda T, Chiarle R, Giaccone G, Bugiani O, Tagliavini F, Frangione B and Ghiso J: Substitutions at codon 22 of Alzheimers abeta peptide induce diverse conformational changes and apoptotic effects in human cerebral endothelial cells. J Biol Chem. 275:27110–27116. 2000.PubMed/NCBI
27	Yang T, Buchan HL, Townsend KJ and Craig RW: MCL-1, a member of the BLC-2 family, is induced rapidly in response to signals for cell differentiation or death, but not to signals for cell proliferation. J Cell Physiol. 166:523–536. 1996. View Article : Google Scholar : PubMed/NCBI
28	Zhou P, Qian L, Bieszczad CK, Noelle R, Binder M, Levy NB and Craig RW: Mcl-1 in transgenic mice promotes survival in a spectrum of hematopoietic cell types and immortalization in the myeloid lineage. Blood. 92:3226–3239. 1998.PubMed/NCBI
29	Reynolds JE, Yang T, Qian L, Jenkinson JD, Zhou P, Eastman A and Craig RW: Mcl-1, a member of the Bcl-2 family, delays apoptosis induced by c-Myc overexpression in Chinese hamster ovary cells. Cancer Res. 54:6348–6352. 1994.PubMed/NCBI
30	Jin S, Mutvei AP, Chivukula IV, Andersson ER, Ramsköld D, Sandberg R, Lee KL, Kronqvist P, Mamaeva V, Ostling P, et al: Non-canonical Notch signaling activates IL-6/JAK/STAT signaling in breast tumor cells and is controlled by p53 and IKKα/IKKβ. Oncogene. 32:4892–4902. 2013. View Article : Google Scholar : PubMed/NCBI
31	Fahmi A, Smart N, Punn A, Jabr R, Marber M and Heads R: p42/p44-MAPK and PI3K are sufficient for IL-6 family cytokines/gp130 to signal to hypertrophy and survival in cardiomyocytes in the absence of JAK/STAT activation. Cell Signal. 25:898–909. 2013. View Article : Google Scholar : PubMed/NCBI
32	Zhang X, Zhang X, Wang C, Li Y, Dong L, Cui L, Wang L, Liu Z, Qiao H, Zhu C, et al: Neuroprotection of early and short-time applying berberine in the acute phase of cerebral ischemia: Up-regulated pAkt, pGSK and pCREB, down-regulated NF-κB expression, ameliorated BBB permeability. Brain Res. 1459:61–70. 2012. View Article : Google Scholar : PubMed/NCBI
33	Nagaraja TN, Keenan KA, Brown SL, Fenstermacher JD and Knight RA: Relative distribution of plasma flow markers and red blood cells across BBB openings in acute cerebral ischemia. Neurol Res. 29:78–80. 2007. View Article : Google Scholar : PubMed/NCBI