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In addition to ammonia, recent studies suggest that inflammation and associated cytokines (CKs) also contribute to the pathogenesis of HE. It was previously established that ammonia induces the mitochondrial permeability transition (mPT) in cultured astrocytes. As CKs have been shown to cause mitochondrial dysfunction in other conditions, we examined whether CKs induce the mPT in cultured astrocytes. Cultures treated with tumor necrosis factor\u2010\u03b1, interleukin\u20101\u03b2, interleukin\u20106, and interferon\u2010\u03b3, individually or in a mixture, resulted in the induction of the mPT in a time\u2010dependent manner. Simultaneous treatment of cultures with a mixture of CKs and ammonia showed a marked additive effect on the mPT. As oxidative stress (OS) is known to induce the mPT, so we examined the effect of CKs and ammonia on hemeoxygenase\u20101 (HO\u20101) protein expression, a marker of OS. Such treatment displayed a synergistic effect in the upregulation of HO\u20101. Antioxidants significantly blocked the additive effects on the mPT by CKs and ammonia, suggesting that OS represents a major mechanism in the induction of the mPT. Treatment of cultures with minocycline, an antiinflammatory agent, which is known to inhibit OS, also diminished the additive effects on the mPT caused by CKs and ammonia. Induction of the mPT in astrocytes appears to represent a major pathogenetic factor in HE, in which CKs and ammonia are critically involved. \u00a9 2011 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jnr.22708","type":"journal-article","created":{"date-parts":[[2011,7,11]],"date-time":"2011-07-11T14:41:35Z","timestamp":1310395295000},"page":"2028-2040","source":"Crossref","is-referenced-by-count":33,"title":["Interaction between cytokines and ammonia in the mitochondrial permeability transition in cultured astrocytes"],"prefix":"10.1002","volume":"89","author":[{"given":"Veronica M.","family":"Alvarez","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kakulavarapu V.","family":"Rama Rao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica","family":"Brahmbhatt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael D.","family":"Norenberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2011,7,11]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4042-03.2004"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-510X(99)00169-0"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.10056"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0303-7207(02)00009-6"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.440070306"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02527755"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/biof.5520080315"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2003.12.007"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-8137.2006.01830.x"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1021989230535"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1023\/B:NERE.0000014834.06405.af"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01311236"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/0891-5849(94)00166-H"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.10181"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(90)91431-F"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1997.69052064.x"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005072-198507000-00003"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.6.3346"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2001.26380"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(93)90111-Y"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(94)00615-6"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.440090306"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(01)00038-1"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2004.06.011"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0120-06.2006"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2009.18"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.63.3.279"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1159\/000112295"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1999.276.2.H496"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2008.09.040"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(94)90183-X"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2004.02420.x"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1979.tb00350.x"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2006.09.008"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00692797"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.14400"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.3171\/jns.1996.85.5.0892"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1006\/excr.1998.4290"},{"key":"e_1_2_6_40_1","first-page":"618","article-title":"A light and electron microscopic study of experimental portal\u2010systemic (ammonia) encephalopathy. 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