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Interleukin 6 and cognitive dysfunction

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Abstract

The interleukin-6 (IL-6) is a pleiotropic cytokine that plays a key role in interaction between immune and nervous system. Although IL-6 has neurotrophic properties and beneficial effects in the CNS, its overexpression is generally detrimental, adding to the pathophysiology associated with CNS disorders. The source of the increase in peripheral IL-6 remains to be established and varies among different pathologies, but has been found to be associated with cognitive dysfunction in several pathologies. This comprehensive review provides an update summary of the studies performed in humans concerning the role of central and peripheral IL-6 in cognitive dysfunction in dementias and in other systemic diseases accompained by cognitive dysfuction such as cardiovascular, liver disease, Behçet’s disease and systemic lupus erythematosus. Further research is needed to correlate specific deficits in IL-6 and its receptors in pathologies characterized by cognitive dysfunction and to understand how systemic IL-6 affects high cerebral function in order to open new directions in pharmacological treatments that modulate IL-6 signalling.

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References

  • ACR (1999) The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum 42:599–608

  • Akaneya Y, Takahashi M, Hatanaka H (1995) Interleukin-1 beta enhances survival and interleukin-6 protects against MPP+ neurotoxicity in cultures of fetal rat dopaminergic neurons. Exp Neurol 136:44–52

    CAS  PubMed  Google Scholar 

  • Akiyama H, Barger S, Barnum S et al (2000) Inflammation and Alzheimer's disease. Neurobiology of Aging 21:383–421

    CAS  PubMed  PubMed Central  Google Scholar 

  • Akman-Demir G, Serdaroglu P, Tasçi B (1999) Clinical patterns of neurological involvement in Behçet's disease: evaluation of 200 patients. The Neuro-Behçet Study Group Brain 122(Pt 11):2171–2182

    Google Scholar 

  • Akman-Demir G, Tüzün E, Içöz S et al (2008) Interleukin-6 in neuro-Behçet's disease: association with disease subsets and long-term outcome. Cytokine 44:373–376

    CAS  PubMed  Google Scholar 

  • Alexander SA, Ren D, Gunn SR et al (2014) Interleukin 6 and apolipoprotein E as predictors of acute brain dysfunction and survival in critical care patients. Am J Crit Care 23:49–57

    PubMed  Google Scholar 

  • Amirzargar A, Shahram F, Nikoopour E et al (2010) Proinflammatory cytokine gene polymorphisms in Behçet's disease. Eur Cytokine Netw 21:292–296

    CAS  PubMed  Google Scholar 

  • Amos A (2002) Remediating deficits of switching attention in patients with acquired brain injury. Brain Inj 16:407–413

    PubMed  Google Scholar 

  • Andriambeloson E, Baillet C, Vitte P-A et al (2006) Interleukin-6 attenuates the development of experimental diabetes-related neuropathy. Neuropathology 26:32–42

    PubMed  Google Scholar 

  • Angelis P, Scharf S, Mander A et al (1998) Serum interleukin-6 and interleukin-6 soluble receptor in Alzheimer's disease. Neurosci Lett 244:106–108

    CAS  PubMed  Google Scholar 

  • Arai T, Mizukami K, Sasaki M et al (1994) Clinicopathological study on a case of neuro-Behçet's disease: in special reference to MRI, SPECT and neuropathological findings. Jpn J Psychiatry Neurol 48:77–84

    CAS  PubMed  Google Scholar 

  • Barres BA, Schmid R, Sendnter M, Raff MC (1993) Multiple extracellular signals are required for long-term oligodendrocyte survival. Development 118:283–295

    CAS  PubMed  Google Scholar 

  • Baskys A, Cheng J-X (2012) Pharmacological prevention and treatment of vascular dementia: approaches and perspectives. Experimental Gerontology 47:887–891

    CAS  PubMed  Google Scholar 

  • Bauer J, Ganter U, Strauss S et al (1992) The participation of interleukin-6 in the pathogenesis of Alzheimer's disease. Res Immunol 143:650–657

    CAS  PubMed  Google Scholar 

  • Berkenbosch F, Biewenga J, Brouns M et al (1992) Cytokines and inflammatory proteins in Alzheimer's disease. Res Immunol 143:657–663

    CAS  PubMed  Google Scholar 

  • Bermejo P, Martín-Aragón S, Benedí J et al (2008) Differences of peripheral inflammatory markers between mild cognitive impairment and Alzheimer's disease. Immunology Letters 117:198–202

    CAS  PubMed  Google Scholar 

  • Biber K, Pinto-Duarte A, Wittendorp MC et al (2008) Interleukin-6 upregulates neuronal adenosine A1 receptors: implications for neuromodulation and neuroprotection. Neuropsychopharmacology 33:2237–2250

    CAS  PubMed  Google Scholar 

  • Blum-Degen D, Müller T, Kuhn W et al (1995) Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer“s and de novo Parkinson”s disease patients. Neurosci Lett 202:17–20

    CAS  PubMed  Google Scholar 

  • Borhani Haghighi A, Ittehadi H, Nikseresht AR et al (2009) CSF levels of cytokines in neuro-Behçet's disease. Clin Neurol Neurosurg 111:507–510

    CAS  PubMed  Google Scholar 

  • Borowicz LM, Goldsborough MA, Selnes OA, McKhann GM (1996) Neuropsychologic change after cardiac surgery: a critical review. J Cardiothorac Vasc Anesth 10:105–112

    CAS  PubMed  Google Scholar 

  • Boulanger MJ, Chow D-C, Brevnova EE, Garcia KC (2003) Hexameric Structure and Assembly of the Interleukin-6/IL-6 {alpha}-Receptor/gp130 Complex. Science Signaling 300:2101–2104

    CAS  Google Scholar 

  • Cauli O, Rodrigo R, Piedrafita B et al (2007) Inflammation and hepatic encephalopathy: ibuprofen restores learning ability in rats with portacaval shunts. Hepatology 46:514–519

    CAS  PubMed  Google Scholar 

  • Cavaco S, da Silva AM, Pinto P et al (2009) Cognitive functioning in Behçet's disease. Ann N Y Acad Sci 1173:217–226

    CAS  PubMed  Google Scholar 

  • Cercy SP, Bylsma FW (1997) Lewy bodies and progressive dementia: a critical review and meta-analysis. J Int Neuropsychol Soc 3:179–194

    CAS  PubMed  Google Scholar 

  • Cesari M, Penninx BWJH, Pahor M et al (2004) Inflammatory markers and physical performance in older persons: the InCHIANTI study. J Gerontol A Biol Sci Med Sci 59:242–248

    PubMed  Google Scholar 

  • Chang HK, Jang WC, Park SB et al (2005) Association between interleukin 6 gene polymorphisms and Behcet's disease in Korean people. Ann Rheum Dis 64:339–340

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chow D-C, He X-L, Snow AL et al (2001) Structure of an Extracellular gp130 Cytokine Receptor Signaling Complex. Science Signaling 291:2150–2155

    CAS  Google Scholar 

  • Chung CP, Oeser A, Solus J et al (2007) Inflammatory mechanisms affecting the lipid profile in patients with systemic lupus erythematosus. J Rheumatol 34:1849–1854

    CAS  PubMed  Google Scholar 

  • Cojocaru IM, Cojocaru M, Miu G, Sapira V (2011) Study of interleukin-6 production in Alzheimer's disease. Rom J Intern Med 49:55–58

    CAS  PubMed  Google Scholar 

  • D'Arcangelo G, Tancredi V, Onofri F et al (2000) Interleukin-6 inhibits neurotransmitter release and the spread of excitation in the rat cerebral cortex. Eur J Neurosci 12:1241–1252

    PubMed  Google Scholar 

  • Davas EM, Tsirogianni A, Kappou I et al (1999) Serum IL-6, TNFalpha, p55 srTNFalpha, p75srTNFalpha, srIL-2alpha levels and disease activity in systemic lupus erythematosus. Clin Rheumatol 18:17–22

    CAS  PubMed  Google Scholar 

  • De Simoni MG, De Luigi A, Gemma L et al (1993) Modulation of systemic interleukin-6 induction by central interleukin-1. Am J Physiol 265:R739–42

    PubMed  Google Scholar 

  • Dellalibera-Joviliano R, Reis Dos ML, Cunha F, De Q, Donadi EA (2003) Kinins and cytokines in plasma and cerebrospinal fluid of patients with neuropsychiatric lupus. J Rheumatol 30:485–492

    CAS  PubMed  Google Scholar 

  • Dendorfer U, Oettgen P, Libermann TA (1994) Multiple regulatory elements in the interleukin-6 gene mediate induction by prostaglandins, cyclic AMP, and lipopolysaccharide. Mol Cell Biol 14:4443–4454

    CAS  PubMed  PubMed Central  Google Scholar 

  • Di Santo E, Alonzi T, Fattori E et al (1996) Overexpression of interleukin-6 in the central nervous system of transgenic mice increases central but not systemic proinflammatory cytokine production. Brain Res 740:239–244

    PubMed  Google Scholar 

  • Dunn AJ (1992) The role of interleukin-1 and tumor necrosis factor alpha in the neurochemical and neuroendocrine responses to endotoxin. Brain Res Bull 29:807–812

    CAS  PubMed  Google Scholar 

  • Dutra LA, Gonçalves CR, Braga-Neto P et al (2012) Atypical manifestations in Brazilian patients with neuro-Behçet's disease. J Neurol 259:1159–1165

    PubMed  Google Scholar 

  • Economos A, Wright CB, Moon YP et al (2013) Interleukin 6 Plasma Concentration Associates with Cognitive Decline: The Northern Manhattan Study. Neuroepidemiology 40:253–259

    PubMed  PubMed Central  Google Scholar 

  • Egashira K (2003) Molecular mechanisms mediating inflammation in vascular disease: special reference to monocyte chemoattractant protein-1. Hypertension 41:834–841

    CAS  PubMed  Google Scholar 

  • Engelhart MJ, Geerlings MI, Meijer J et al (2004) Inflammatory proteins in plasma and the risk of dementia: the rotterdam study. Arch Neurol 61:668–672

    PubMed  Google Scholar 

  • Ershler WB, Keller ET (2000) Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu Rev Med 51:245–270

    CAS  PubMed  Google Scholar 

  • Fried LP, Guralnik JM (1997) Disability in older adults: evidence regarding significance, etiology, and risk. J Am Geriatr Soc 45:92–100

    CAS  PubMed  Google Scholar 

  • Gadient RA, Otten U (1994a) Identification of interleukin-6 (IL-6)-expressing neurons in the cerebellum and hippocampus of normal adult rats. Neurosci Lett 182:243–246

    CAS  PubMed  Google Scholar 

  • Gadient RA, Otten U (1993) Differential expression of interleukin-6 (IL-6) and interleukin-6 receptor (IL-6R) mRNAs in rat hypothalamus. Neurosci Lett 153:13–16

    CAS  PubMed  Google Scholar 

  • Gadient RA, Otten U (1994b) Expression of interleukin-6 (IL-6) and interleukin-6 receptor (IL-6R) mRNAs in rat brain during postnatal development. Brain Res 637:10–14

    CAS  PubMed  Google Scholar 

  • Gadient RA, Otten UH (1997) Interleukin-6 (IL-6)–a molecule with both beneficial and destructive potentials. Prog Neurobiol 52:379–390

    CAS  PubMed  Google Scholar 

  • Garcia-Oscos F, Salgado H, Hall S et al (2012) The stress-induced cytokine interleukin-6 decreases the inhibition/excitation ratio in the rat temporal cortex via trans-signaling. Biological Psychiatry 71:574–582

    CAS  PubMed  Google Scholar 

  • Gauldie J, Sauder DN, McAdam KP, Dinarello CA (1987) Purified interleukin-1 (IL-1) from human monocytes stimulates acute-phase protein synthesis by rodent hepatocytes in vitro. Immunology 60:203–207

    CAS  PubMed  PubMed Central  Google Scholar 

  • Girotti M, Donegan JJ, Morilak DA (2012) Influence of hypothalamic IL-6/gp130 receptor signaling on the HPA axis response to chronic stress. Psychoneuroendocrinology 38:1158–1169

    PubMed  PubMed Central  Google Scholar 

  • Goodman MN (1994) Interleukin-6 induces skeletal muscle protein breakdown in rats. Proc Soc Exp Biol Med 205:182–185

    CAS  PubMed  Google Scholar 

  • Gómez-Tortosa E, Gonzalo I, Fanjul S et al (2003) Cerebrospinal fluid markers in dementia with lewy bodies compared with Alzheimer disease. Arch Neurol 60:1218–1222

    PubMed  Google Scholar 

  • Gruol DL, Nelson TE (1997) Physiological and pathological roles of interleukin-6 in the central nervous system. Mol Neurobiol 15:307–339

    CAS  PubMed  Google Scholar 

  • Guzmán C, Hallal-Calleros C (2010) Interleukin-6: a cytokine with a pleiotropic role in the neuroimmunoendocrine network. The Open Neuroendocrinology Journal 3:152–160

    Google Scholar 

  • Gündüz T, Emir Ö, Kürtüncü M et al (2012) Cognitive impairment in neuro-Behcet's disease and multiple sclerosis: a comparative study. Int J Neurosci 122:650–656

    PubMed  Google Scholar 

  • Hama T, Kushima Y, Miyamoto M et al (1991) Interleukin-6 improves the survival of mesencephalic catecholaminergic and septal cholinergic neurons from postnatal, two-week-old rats in cultures. Neuroscience 40:445–452

    CAS  PubMed  Google Scholar 

  • Hammeke TA, Hastings JE (1988) Neuropsychologic alterations after cardiac operation. J Thorac Cardiovasc Surg 96:326–331

    CAS  PubMed  Google Scholar 

  • Hampel H, Haslinger A, Scheloske M et al (2005) Pattern of interleukin-6 receptor complex immunoreactivity between cortical regions of rapid autopsy normal and Alzheimer's disease brain. Eur Arch Psychiatry Clin Neurosci 255:269–278

    PubMed  Google Scholar 

  • Hanly JG, Cassell K, Fisk JD (1997) Cognitive function in systemic lupus erythematosus: results of a 5-year prospective study. Arthritis Rheum 40:1542–1543

    CAS  PubMed  Google Scholar 

  • Hanly JG, Su L, Omisade A et al (2012) Screening for cognitive impairment in systemic lupus erythematosus. J Rheumatol 39:1371–1377

    PubMed  Google Scholar 

  • Hanly JG, Urowitz MB, Sanchez-Guerrero J et al (2007) Neuropsychiatric events at the time of diagnosis of systemic lupus erythematosus: an international inception cohort study. Arthritis Rheum 56:265–273

    CAS  PubMed  Google Scholar 

  • Hay EM, Huddy A, Black D et al (1994) A prospective study of psychiatric disorder and cognitive function in systemic lupus erythematosus. Ann Rheum Dis 53:298–303

    CAS  PubMed  PubMed Central  Google Scholar 

  • Heinrich PC, Behrmann I, Müller-Newen G et al (1998) Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 334(Pt 2):297–314

    CAS  PubMed  PubMed Central  Google Scholar 

  • Henriksen L, Hjelms E, Lindeburgh T (1983) Brain hyperperfusion during cardiac operations. Cerebral blood flow measured in man by intra-arterial injection of xenon 133: evidence suggestive of intraoperative microembolism. J Thorac Cardiovasc Surg 86:202–208

    CAS  PubMed  Google Scholar 

  • Hirohata S (1996) Coping with pathological changes in nerves and blood vessels in collagen disease–CNS lupus. Nippon Naika Gakkai Zasshi 85:1816–1821

    CAS  PubMed  Google Scholar 

  • Hirohata S, Isshi K, Oguchi H et al (1997) Cerebrospinal fluid interleukin-6 in progressive Neuro-Behçet's syndrome. Clin Immunol Immunopathol 82:12–17

    CAS  PubMed  Google Scholar 

  • Hirohata S, Kikuchi H (2003) Behçet's disease. Arthritis Res Ther 5:139–146

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hirohata S, Kikuchi H (2012) Changes in biomarkers focused on differences in disease course or treatment in patients with neuro-Behçet's disease. Intern Med 51:3359–3365

    PubMed  Google Scholar 

  • Hirohata S, Miyamoto T (1990) Elevated levels of interleukin-6 in cerebrospinal fluid from patients with systemic lupus erythematosus and central nervous system involvement. Arthritis Rheum 33:644–649

    CAS  PubMed  Google Scholar 

  • Huell M, Strauss S, Volk B et al (1995) Interleukin-6 is present in early stages of plaque formation and is restricted to the brains of Alzheimer's disease patients. Acta Neuropathol 89:544–551

    CAS  PubMed  Google Scholar 

  • Hull M, Berger M, Volk B, Bauer J (1996a) Occurrence of interleukin-6 in cortical plaques of Alzheimer's disease patients may precede transformation of diffuse into neuritic plaques. Ann N Y Acad Sci 777:205–212

    CAS  PubMed  Google Scholar 

  • Hull M, Strauss S, Berger M et al (1996b) Inflammatory mechanisms in Alzheimer's disease. Eur Arch Psychiatry Clin Neurosci 246:124–128

    CAS  PubMed  Google Scholar 

  • Imamura K, Hishikawa N, Ono K et al (2004) Cytokine production of activated microglia and decrease in neurotrophic factors of neurons in the hippocampus of Lewy body disease brains. Acta Neuropathol 109:141–150

    PubMed  Google Scholar 

  • Inaba G (1984) Revised criteria for the diagnosis of Behçet's disease. Ryumachi 24:135–141

    CAS  PubMed  Google Scholar 

  • Jain L, Sharma BC, Sharma P et al (2012) Serum endotoxin and inflammatory mediators in patients with cirrhosis and hepatic encephalopathy. Dig Liver Dis 44:1027–1031

    CAS  PubMed  Google Scholar 

  • Jellinger KA (2009) Intrathecal levels of IL-6 in Alzheimer’s disease. J Neurol 257:142–142

    Google Scholar 

  • Jenny NS, French B, Arnold AM et al (2012) Long-term assessment of inflammation and healthy aging in late life: the Cardiovascular Health Study All Stars. J Gerontol A Biol Sci Med Sci 67:970–976

    PubMed  PubMed Central  Google Scholar 

  • Ji R, Tian S, Lu HJ et al (2013) TAM receptors affect adult brain neurogenesis by negative regulation of microglial cell activation. J Immunol 191:6165–6177

    CAS  PubMed  Google Scholar 

  • Jia JP, Meng R, Sun YX et al (2005) Cerebrospinal fluid tau, Abeta1-42 and inflammatory cytokines in patients with Alzheimer's disease and vascular dementia. Neurosci Lett 383:12–16

    CAS  PubMed  Google Scholar 

  • Jüttler E, Tarabin V, Schwaninger M (2002) Interleukin-6 (IL-6): a possible neuromodulator induced by neuronal activity. Neuroscientist 8:268–275

    PubMed  Google Scholar 

  • Kalman J, Juhasz A, Laird G et al (2009) Serum interleukin-6 levels correlate with the severity of dementia in Down syndrome and in Alzheimer's disease. Acta Neurol Scand 96:236–240

    Google Scholar 

  • Kalman J, Juhasz A, Laird G et al (1997) Serum interleukin-6 levels correlate with the severity of dementia in Down syndrome and in Alzheimer's disease. Acta Neurol Scand 96:236–240

    CAS  PubMed  Google Scholar 

  • Kálmán J, Juhász A, Bogáts G et al (2006) Elevated levels of inflammatory biomarkers in the cerebrospinal fluid after coronary artery bypass surgery are predictors of cognitive decline. Neurochemistry International 48:177–180

    PubMed  Google Scholar 

  • Kent SS, Kelley KWK, Dantzer RR (1992) Effects of lipopolysaccharide on food-motivated behavior in the rat are not blocked by an interleukin-1 receptor antagonist. Neurosci Lett 145:83–86

    CAS  PubMed  Google Scholar 

  • Klein MA, Möller JC, Jones LL et al (1997) Impaired neuroglial activation in interleukin-6 deficient mice. Glia 19:227–233

    CAS  PubMed  Google Scholar 

  • Kopf M, Baumann H, Freer G et al (1994) Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature 368:339–342

    CAS  PubMed  Google Scholar 

  • Kossmann T, Hans V, Imhof HG et al (1996) Interleukin-6 released in human cerebrospinal fluid following traumatic brain injury may trigger nerve growth factor production in astrocytes. Brain Res 713:143–152

    CAS  PubMed  Google Scholar 

  • Kozora E, Ellison MC, West S (2004) Reliability and validity of the proposed American College of Rheumatology neuropsychological battery for systemic lupus erythematosus. Arthritis Rheum 51:810–818

    PubMed  Google Scholar 

  • Kozora E, Filley CM, Zhang L et al (2012) Immune function and brain abnormalities in patients with systemic lupus erythematosus without overt neuropsychiatric manifestations. Lupus 21:402–411

    CAS  PubMed  Google Scholar 

  • Krabbe KS, Pedersen M, Bruunsgaard H (2004) Inflammatory mediators in the elderly. Experimental Gerontology 39:687–699

    CAS  PubMed  Google Scholar 

  • Krabbe KS, Reichenberg A, Yirmiya R et al (2005) Low-dose endotoxemia and human neuropsychological functions. BRAIN, BEHAVIOUR, AND IMMUNITY 19:453–460

    CAS  Google Scholar 

  • Kushima Y, Hama T, Hatanaka H (1992) Interleukin-6 as a neurotrophic factor for promoting the survival of cultured catecholaminergic neurons in a chemically defined medium from fetal and postnatal rat midbrains. Neurosci Res 13:267–280

    CAS  PubMed  Google Scholar 

  • Kushima Y, Hatanaka H (1992) Interleukin-6 and leukemia inhibitory factor promote the survival of acetylcholinesterase-positive neurons in culture from embryonic rat spinal cord. Neurosci Lett 143:110–114

    CAS  PubMed  Google Scholar 

  • Lanzrein AS, Johnston CM, Perry VH et al (1998) Longitudinal study of inflammatory factors in serum, cerebrospinal fluid, and brain tissue in Alzheimer disease: interleukin-1beta, interleukin-6, interleukin-1 receptor antagonist, tumor necrosis factor-alpha, the soluble tumor necrosis factor receptors I and II, and alpha1-antichymotrypsin. Alzheimer Dis Assoc Disord 12:215–227

    CAS  PubMed  Google Scholar 

  • Licastro F, Grimaldi LME, Bonafè M et al (2003) Interleukin-6 gene alleles affect the risk of Alzheimer's disease and levels of the cytokine in blood and brain. NBA 24:921–926

    CAS  Google Scholar 

  • Licastro F, Pedrini S, Caputo L et al (2000) Increased plasma levels of interleukin-1, interleukin-6 and alpha-1-antichymotrypsin in patients with Alzheimer's disease: peripheral inflammation or signals from the brain? Journal of Neuroimmunology 103:97–102

    CAS  PubMed  Google Scholar 

  • Lim L, Lippe S, Silverman E (2013) Effect of autoimmune diseases on cognitive function. Handb Clin Neurol 112:1275–1283

    PubMed  Google Scholar 

  • Linker-Israeli M, Deans RJ, Wallace DJ et al (1991) Elevated levels of endogenous IL-6 in systemic lupus erythematosus. A putative role in pathogenesis J Immunol 147:117–123

    CAS  Google Scholar 

  • Luo M, Li L, Yang E-N, Cao W-K (2012) Relationship between interleukin-6 and ammonia in patients with minimal hepatic encephalopathy due to liver cirrhosis. Hepatol Res 42:1202–1210

    CAS  PubMed  Google Scholar 

  • Marsland AL, Gianaros PJ, Abramowitch SM et al (2008) Interleukin-6 Covaries Inversely with Hippocampal Grey Matter Volume in Middle-Aged Adults. Biological Psychiatry 64:484–490

    CAS  PubMed  PubMed Central  Google Scholar 

  • Martínez M, Fernández-Vivancos E, Frank A et al (2000) Increased cerebrospinal fluid fas (Apo-1) levels in Alzheimer's disease. Relationship with IL-6 concentrations. Brain Res 869:216–219

    PubMed  Google Scholar 

  • Mastorakos G, Ilias I (2006) Interleukin-6: a cytokine and/or a major modulator of the response to somatic stress. Ann N Y Acad Sci 1088:373–381

    CAS  PubMed  Google Scholar 

  • May LT, Santhanam U, Sehgal PB (1991) On the multimeric nature of natural human interleukin-6. J Biol Chem 266:9950–9955

    CAS  PubMed  Google Scholar 

  • März P, Heese K, Hock C et al (1997) Interleukin-6 (IL-6) and soluble forms of IL-6 receptors are not altered in cerebrospinal fluid of Alzheimer's disease patients. Neurosci Lett 239:29–32

    PubMed  Google Scholar 

  • McKeith IG, Galasko D, Kosaka K et al (1996) Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 47:1113–1124

    CAS  PubMed  Google Scholar 

  • Mege JL, Dilsen N, Sanguedolce V et al (1993) Overproduction of monocyte derived tumor necrosis factor alpha, interleukin (IL) 6, IL-8 and increased neutrophil superoxide generation in Behçet's disease. A comparative study with familial Mediterranean fever and healthy subjects J Rheumatol 20:1544–1549

    CAS  Google Scholar 

  • Monastero R, Camarda C, Pipia C et al (2004) Cognitive impairment in Behçet's disease patients without overt neurological involvement. Journal of the Neurological Sciences 220:99–104

    PubMed  Google Scholar 

  • Montagnese S, Biancardi A, Schiff S et al (2011) Different biochemical correlates for different neuropsychiatric abnormalities in patients with cirrhosis. Hepatology 53:558–566

    CAS  PubMed  Google Scholar 

  • Monje ML, Toda H, Palmer TD (2003) Inflammatory blockade restores adult hippocampal neurogenesis. Science 302:1760–1765

    CAS  PubMed  Google Scholar 

  • Montoliu C, Cauli O, Urios A et al (2011) 3-nitro-tyrosine as a peripheral biomarker of minimal hepatic encephalopathy in patients with liver cirrhosis. Am J Gastroenterol 106:1629–1637

    CAS  PubMed  Google Scholar 

  • Montoliu C, Piedrafita B, Serra MA et al (2009) IL-6 and IL-18 in blood may discriminate cirrhotic patients with and without minimal hepatic encephalopathy. J Clin Gastroenterol 43:272–279

    CAS  PubMed  Google Scholar 

  • Mooijaart SP, Sattar N, Trompet S et al (2013) Circulating interleukin-6 concentration and cognitive decline in old age: the PROSPER study. J Intern Med 274:77–85

    CAS  PubMed  Google Scholar 

  • Murphy PG, Grondin J, Altares M, Richardson PM (1995) Induction of interleukin-6 in axotomized sensory neurons. J Neurosci 15:5130–5138

    CAS  PubMed  Google Scholar 

  • Naitoh Y, Fukata J, Tominaga T et al (1988) Interleukin-6 stimulates the secretion of adrenocorticotropic hormone in conscious, freely-moving rats. Biochem Biophys Res Commun 155:1459–1463

    CAS  PubMed  Google Scholar 

  • Nelson TE, Netzeband JG, Gruol DL (2004) Chronic interleukin-6 exposure alters metabotropic glutamate receptor-activated calcium signalling in cerebellar Purkinje neurons. Eur J Neurosci 20:2387–2400

    PubMed  Google Scholar 

  • Nybo L, Nielsen B, Pedersen BK et al (2002) Interleukin-6 release from the human brain during prolonged exercise. J Physiol (Lond) 542:991–995

    CAS  Google Scholar 

  • Oktem-Tanör O, Baykan-Kurt B, Gürvit IH et al (1999) Neuropsychological follow-up of 12 patients with neuro-Behçet disease. J Neurol 246:113–119

    PubMed  Google Scholar 

  • Peters M, Müller AM, Rose-John S (1998) Interleukin-6 and soluble interleukin-6 receptor: direct stimulation of gp130 and hematopoiesis. Blood 92:3495–3504

    CAS  PubMed  Google Scholar 

  • Pola R, Flex A, Gaetani E et al (2002) The −174 G/C polymorphism of the interleukin-6 gene promoter and essential hypertension in an elderly Italian population. J Hum Hypertens 16:637–640

    CAS  PubMed  Google Scholar 

  • Pugsley W, Klinger L, Paschalis C et al (1994) The impact of microemboli during cardiopulmonary bypass on neuropsychological functioning. Stroke 25:1393–1399

    CAS  PubMed  Google Scholar 

  • Qiu Z, Sweeney DD, Netzeband JG, Gruol DL (1998) Chronic interleukin-6 alters NMDA receptor-mediated membrane responses and enhances neurotoxicity in developing CNS neurons. J Neurosci 18:10445–10456

    CAS  PubMed  Google Scholar 

  • Rafnsson SB, Deary IJ, Smith FB et al (2007) Cardiovascular diseases and decline in cognitive function in an elderly community population: the Edinburgh Artery Study. Psychosom Med 69:425–434

    PubMed  Google Scholar 

  • Rose-John S (2012) IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6. Int J Biol Sci 8:1237–1247

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rosenblat JD, Cha DS, Mansur RB, McIntyre RS (2014) Inflamed moods: A review of the interactions between inflammation and mood disorders. Prog Neuropsychopharmacol Biol Psychiatry 53C:23–34

    Google Scholar 

  • Rothenburg LS, Herrmann N, Swardfager W et al (2010) The relationship between inflammatory markers and post stroke cognitive impairment. J Geriatr Psychiatry Neurol 23:199–205

    PubMed  Google Scholar 

  • Sakane T, Takeno M, Suzuki N, Inaba G (1999) Behçet's disease. N Engl J Med 341:1284–1291

    CAS  PubMed  Google Scholar 

  • Sala G, Galimberti G, Canevari C et al (2003) Peripheral cytokine release in Alzheimer patients: correlation with disease severity. Neurobiology of Aging 24:909–914

    CAS  PubMed  Google Scholar 

  • Savageau JA, Stanton BA, Jenkins CD, Frater RW (1982) Neuropsychological dysfunction following elective cardiac operation. II A six-month reassessment J Thorac Cardiovasc Surg 84:595–600

    CAS  Google Scholar 

  • Sawada M, Imamura K, Nagatsu T (2006) Role of cytokines in inflammatory process in Parkinson's disease. J Neural Transm Suppl 70:373–381

    CAS  PubMed  Google Scholar 

  • Sawada M, Suzumura A, Marunouchi T (1995) Cytokine network in the central nervous system and its roles in growth and differentiation of glial and neuronal cells. Int J Dev Neurosci 13:253–264

    CAS  PubMed  Google Scholar 

  • Sayinalp N, Ozcebe OI, Ozdemir O et al (1996) Cytokines in Behçet's disease. J Rheumatol 23:321–322

    CAS  PubMed  Google Scholar 

  • Sánchez-López F, Tasset I, Agüera E et al (2012) Oxidative stress and inflammation biomarkers in the blood of patients with Huntington's disease. Neurol Res 34:721–724

    PubMed  Google Scholar 

  • Schöbitz B, de Kloet ER, Holsboer F (1994) Gene expression and function of interleukin 1, interleukin 6 and tumor necrosis factor in the brain. Prog Neurobiol 44:397–432

    PubMed  Google Scholar 

  • Schöbitz B, de Kloet ER, Sutanto W, Holsboer F (1993) Cellular localization of interleukin 6 mRNA and interleukin 6 receptor mRNA in rat brain. Eur J Neurosci 5:1426–1435

    PubMed  Google Scholar 

  • Shalit F, Sredni B, Stern L et al (1994) Elevated interleukin-6 secretion levels by mononuclear cells of Alzheimer's patients. Neurosci Lett 174:130–132

    CAS  PubMed  Google Scholar 

  • Shapiro LS, Farrell J, Haghighi AB (2012) Tocilizumab treatment for neuro-Behcet's disease, the first report. Clin Neurol Neurosurg 114:297–298

    PubMed  Google Scholar 

  • Shaw PJ, Bates D, Cartlidge NE et al (1987) Long-term intellectual dysfunction following coronary artery bypass graft surgery: a six month follow-up study. Q J Med 62:259–268

    CAS  PubMed  Google Scholar 

  • Shibata N, Ohnuma T, Takahashi T et al (2002) Effect of IL-6 polymorphism on risk of Alzheimer disease: genotype-phenotype association study in Japanese cases. Am J Med Genet 114:436–439

    PubMed  Google Scholar 

  • Shrikant P, Weber E, Jilling T, Benveniste EN (1995) Intercellular adhesion molecule-1 gene expression by glial cells. Differential mechanisms of inhibition by IL-10 and IL-6. J Immunol 155:1489–1501

    CAS  PubMed  Google Scholar 

  • Silvestroni A, Faull RLM, Strand AD, Möller T (2009) Distinct neuroinflammatory profile in post-mortem human Huntington's disease. Neuroreport 20:1098–1103

    PubMed  Google Scholar 

  • Singh VK, Guthikonda P (1997) Circulating cytokines in Alzheimer's disease. J Psychiatr Res 31:657–660

    CAS  PubMed  Google Scholar 

  • Spronk PE, ter Borg EJ, Limburg PC, Kallenberg CG (1992) Plasma concentration of IL-6 in systemic lupus erythematosus; an indicator of disease activity? Clin Exp Immunol 90:106–110

    CAS  PubMed  PubMed Central  Google Scholar 

  • Steffensen SC, Campbell IL, Henriksen SJ (1994) Site-specific hippocampal pathophysiology due to cerebral overexpression of interleukin-6 in transgenic mice. Brain Res 652:149–153

    CAS  PubMed  Google Scholar 

  • Stojanovic A, Martorell L, Montalvo I et al (2014) Increased serum interleukin-6 levels in early stages of psychosis: associations with at-risk mental states and the severity of psychotic symptoms. Psychoneuroendocrinology 41:23–32

    CAS  PubMed  Google Scholar 

  • Strauss S, Bauer J, Ganter U et al (1992) Detection of interleukin-6 and alpha 2-macroglobulin immunoreactivity in cortex and hippocampus of Alzheimer's disease patients. Lab Invest 66:223–230

    CAS  PubMed  Google Scholar 

  • Stys PK, Jiang Q (2002) Calpain-dependent neurofilament breakdown in anoxic and ischemic rat central axons. Neurosci Lett 328:150–154

    CAS  PubMed  Google Scholar 

  • Suzuki S, Tanaka K, Nagata E et al (1999) Cerebral neurons express interleukin-6 after transient forebrain ischemia in gerbils. Neurosci Lett 262:117–120

    CAS  PubMed  Google Scholar 

  • Tancredi V, D'Antuono M, Cafè C et al (2000) The inhibitory effects of interleukin-6 on synaptic plasticity in the rat hippocampus are associated with an inhibition of mitogen-activated protein kinase ERK. J Neurochem 75:634–643

    CAS  PubMed  Google Scholar 

  • Tarkowski E, Blennow K, Wallin A, Tarkowski A (1999) Intracerebral production of tumor necrosis factor-alpha, a local neuroprotective agent, in Alzheimer disease and vascular dementia. J Clin Immunol 19:223–230

    CAS  PubMed  Google Scholar 

  • Tarkowski E, Liljeroth AM, Minthon L et al (2003) Cerebral pattern of pro- and anti-inflammatory cytokines in dementias. Brain Res Bull 61:255–260

    CAS  PubMed  Google Scholar 

  • Tatemichi TK, Desmond DW, Stern Y et al (1994) Cognitive impairment after stroke: frequency, patterns, and relationship to functional abilities. J Neurol Neurosurg Psychiatr 57:202–207

    CAS  PubMed  PubMed Central  Google Scholar 

  • Toulmond S, Vige X, Fage D, Benavides J (1992) Local infusion of interleukin-6 attenuates the neurotoxic effects of NMDA on rat striatal cholinergic neurons. Neurosci Lett 144:49–52

    CAS  PubMed  Google Scholar 

  • Trysberg E, Carlsten H, Tarkowski A (2000) Intrathecal cytokines in systemic lupus erythematosus with central nervous system involvement. Lupus 9:498–503

    CAS  PubMed  Google Scholar 

  • Urbaniak P, Hasler P, Kretzschmar S (2012) Refractory neuro-Behçet treated by tocilizumab: a case report. Clin Exp Rheumatol 30:S73–5

    CAS  PubMed  Google Scholar 

  • Vallières L, Campbell IL, Gage FH, Sawchenko PE (2002) Reduced hippocampal neurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6. J Neurosci 22:486–492

    PubMed  Google Scholar 

  • Vallières L, Rivest S (1997) Regulation of the genes encoding interleukin-6, its receptor, and gp130 in the rat brain in response to the immune activator lipopolysaccharide and the proinflammatory cytokine interleukin-1beta. J Neurochem 69:1668–1683

    PubMed  Google Scholar 

  • van Duijn CM, Hofman A, Nagelkerken L (1990) Serum levels of interleukin-6 are not elevated in patients with Alzheimer's disease. Neurosci Lett 108:350–354

    PubMed  Google Scholar 

  • Varghese JN, Moritz RL, Lou M-Z et al (2002) Structure of the extracellular domains of the human interleukin-6 receptor alpha -chain. Proc Natl Acad Sci USA 99:15959–15964

    CAS  PubMed  PubMed Central  Google Scholar 

  • Visser M, Pahor M, Taaffe DR et al (2002) Relationship of interleukin-6 and tumor necrosis factor-alpha with muscle mass and muscle strength in elderly men and women: the Health ABC Study. J Gerontol A Biol Sci Med Sci 57:M326–32

    PubMed  Google Scholar 

  • Wada-Isoe K, Wakutani Y, Urakami K, Nakashima K (2004) Elevated interleukin-6 levels in cerebrospinal fluid of vascular dementia patients. Acta Neurol Scand 110:124–127

    CAS  PubMed  Google Scholar 

  • Wallenius K, Wallenius V, Sunter D et al (2002) Intracerebroventricular interleukin-6 treatment decreases body fat in rats. Biochem Biophys Res Commun 293:560–565

    CAS  PubMed  Google Scholar 

  • Wang J, Dunn AJ (1998) Mouse interleukin-6 stimulates the HPA axis and increases brain tryptophan and serotonin metabolism. Neurochemistry International 33:143–154

    CAS  PubMed  Google Scholar 

  • Waterloo K, Omdal R, Husby G, Mellgren SI (2002) Neuropsychological function in systemic lupus erythematosus: a five-year longitudinal study. Rheumatology (Oxford) 41:411–415

    CAS  Google Scholar 

  • Weaver JD, Huang M-H, Albert M et al (2002) Interleukin-6 and risk of cognitive decline: MacArthur studies of successful aging. Neurology 59:371–378

    CAS  PubMed  Google Scholar 

  • Wei H, Alberts I, Li X (2013) Brain IL-6 and autism. Neuroscience 252:320–325

    CAS  PubMed  Google Scholar 

  • Wood JA, Wood PL, Ryan R et al (1993) Cytokine indices in Alzheimer's temporal cortex: no changes in mature IL-1 beta or IL-1RA but increases in the associated acute phase proteins IL-6, alpha 2-macroglobulin and C-reactive protein. Brain Res 629:245–252

    CAS  PubMed  Google Scholar 

  • Wu Y, Shaghaghi EK, Jacquot C et al (1999) Synergism between interleukin-6 and interleukin-1beta in hypothalamic serotonin release: a reverse in vivo microdialysis study in F344 rats. Eur Cytokine Netw 10:57–64

    CAS  PubMed  Google Scholar 

  • Xiao E, Xia L, Ferin M, Wardlaw SL (1999) Intracerebroventricular injection of interleukin-1 stimulates the release of high levels of interleukin-6 and interleukin-1 receptor antagonist into peripheral blood in the primate. Journal of Neuroimmunology 97:70–76

    CAS  PubMed  Google Scholar 

  • Yaffe K, Kanaya A, Lindquist K et al (2004) The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA 292:2237–2242

    CAS  PubMed  Google Scholar 

  • Yamada M, Hatanaka H (1994) Interleukin-6 protects cultured rat hippocampal neurons against glutamate-induced cell death. Brain Res 643:173–180

    CAS  PubMed  Google Scholar 

  • Yamakawa Y, Sugita Y, Nagatani T et al (1996) Interleukin-6 (IL-6) in patients with Behçet's disease. J Dermatol Sci 11:189–195

    CAS  PubMed  Google Scholar 

  • Zalcman S, Green-Johnson JM, Murray L et al (1994) Cytokine-specific central monoamine alterations induced by interleukin-1, −2 and −6. Brain Res 643:40–49

    CAS  PubMed  Google Scholar 

  • Zhang J, Terreni L, De Simoni MG, Dunn AJ (2001) Peripheral interleukin-6 administration increases extracellular concentrations of serotonin and the evoked release of serotonin in the rat striatum. Neurochemistry International 38:303–308

    CAS  PubMed  Google Scholar 

  • Zhao S-J, Guo C-N, Wang M-Q et al (2012) Serum levels of inflammation factors and cognitive performance in amnestic mild cognitive impairment: a Chinese clinical study. Cytokine 57:221–225

    CAS  PubMed  Google Scholar 

  • Zhong J, Dietzel ID, Wahle P et al (1999) Sensory impairments and delayed regeneration of sensory axons in interleukin-6-deficient mice. J Neurosci 19:4305–4313

    CAS  PubMed  Google Scholar 

  • Zuliani G, Guerra G, Ranzini M et al (2007a) High interleukin-6 plasma levels are associated with functional impairment in older patients with vascular dementia. Int J Geriatr Psychiatry 22:305–311

    CAS  PubMed  Google Scholar 

  • Zuliani G, Ranzini M, Guerra G, et al. (2007b) Plasma cytokines profile in older subjects with late onset Alzheimer’s disease or vascular dementia. J Psychiatr Res 41:686–693

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Trapero, I., Cauli, O. Interleukin 6 and cognitive dysfunction. Metab Brain Dis 29, 593–608 (2014). https://doi.org/10.1007/s11011-014-9551-2

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