Die Bedeutung des TNF-α-Systems für Erkrankungen des Gehirns

Zusammenfassung

Es gibt vielfache Hinweise in der Literatur darauf, dass Veränderungen des Immunsystems oder spezifischer ausgedrückt des Zytokinsystems, zu dem auch der Tumornekrosefaktor-alpha (TNF-α) zählt, an der Entstehung neurologischer Erkrankungen aus dem entzündlichen und neurodegenerativen Formenkreis wie der Multiplen Sklerose, dem Morbus Alzheimer und Morbus Parkinson sowie psychiatrischer Erkrankungen wie der Depression, Schizophrenie und Narkolepsie beteiligt sind. Zudem bestehen Zusammenhänge zwischen Zytokinkonzentrationen im Serum und dem Risiko zereobrovaskulärer Ereignisse. Auch Körpergewicht, Alter und neuroendokrinologische Mechanismen haben einen starken Einfluss auf die Plasmakonzentrationen von TNF-α und seiner löslichen Rezeptoren (sTNF-Rs). TNF-α könnte zur Pathogenese dieser Erkrankungen durch eine Aktivierung der Hypothalamus-Hypophysen-Nebennierenrinden-Achse (HPA-Achse), eine Aktivierung von Serotonintransportern, eine Stimulation der Indolamin-2,3-Dioxygenase, die zur Tryptophandepletion führt, einen immunologisch vermittelten Neuronenuntergang oder neurotoxische Effekte durch Glutamatausschüttung beitragen. Auch eine psychopharmakologische Therapie beeinflusst das Immunsystem. Bei der antipsychotischen Therapie ist möglicherweise ein Teil der Wirkung bestimmter Antipsychotika über eine Induktion inflammatorischer Zytokine vermittelt. Es ist zu wünschen, dass diese Überlegungen in naher Zukunft zu immunmodulatorischen Therapiestrategien für psychisch kranke Patienten führen.

Abstract

Changes regarding the immune system and specifically the cytokine system, of which tumor necrosis factor-alpha (TNF-α) is a part, have been shown to be involved in the development of neurological and psychiatric disorders such as multiple sclerosis, Parkinson‘s and Alzheimer‘s disease, depression, schizophrenia or narcolepsy. Besides, there is evidence that the risk of stroke correlates with the serum concentrations of different cytokines. Additionally, body weight, age and neuroendocrinological mechanism have a strong influence upon plasma levels of TNF-α and its soluble receptors (sTNF-Rs). TNF-α might contribute to the pathogenesis of these diseases by an activation of the hypothalamo-pituitary-adrenocortical (HPA) axis, an activation of neuronal serotonin transporters, the stimulation of the indoleamine 2,3-dioxygenase which leads to tryptophan depletion, by immunologically mediated destruction of neurons, or neurotoxic release of glutamate. Psychotropic drugs influence the TNF-α system, too. During psychopharmacological treatment of schizophrenia, some antipsychotics might act on neurotransmitter metabolism via inducing the proinflammatory cytokine system. Hopefully, these hypotheses may lead to new therapeutical strategies for psychiatric patients in the near future.

Schlüsselwörter

TNF-α - Depression - Schizophrenie - Narkolepsie - Psychopharmaka - Zytokin - Entzündung

Key words

TNF-α - depression - schizophrenia - narcolepsy - psychopharmacology - cytokine - inflammation

Literatur

• 1 Himmerich H. Neuroimmunologie. Holsboer F, Gründer G, Benkert O Handbuch der Psychopharmakologie Heidelberg; Springer 2007 1. Aufl: 369-374
• 2 Fricchione G, Daly R, Rogers M P. et al . Neuroimmunologic influences in neuropsychiatric and psychophysiologic disorders.  Acta Pharmacol Sin. 2001;  22 577-587
• 3 Dantzer R. Cytokine-induced sickness behaviour: a neuroimmune response to activation of innate immunity.  Eur J Pharmacol. 2004;  500 399-411
• 4 Harenberg Lexikon der Nobelpreisträger. Dortmund; Harenberg Lexikon Verlag 2000
• 5 Carswell E A, Old L J, Kassel R L. et al . An endotoxin-induced serum factor that causes necrosis of tumors.  Proc Natl Acad Sci USA. 1975;  72 3666-3670
• 6 Clark I A. How TNF was recognized as a key mechanism of disease.  Cytokine Growth Factor Rev. 2007;  18 335-343
• 7 Goodsell D S. The molecular perspective: tumor necrosis factor.  Oncologist. 2006;  11 83-84
• 8 Fiers W. Tumor necrosis factor. Characterization at the molecular, cellular and in vivo level.  FEBS Lett. 1991;  285 199-212
• 9 Perskidskiî I uV, Barshteiîn I uA. Biological manifestations of the tumor necrosis factor effect and its role in the pathogenesis of various diseases.  Arkh Patol. 1992;  54 5-10
• 10 Himmerich H. Activity of the TNF-alpha system in patients with brain disorders and during psychopharmacological treatment.  Curr Pharmaceut Anal. 2007;  3 1-5
• 11 Wajant H, Pfizenmaier K, Scheurich P. Tumor necrosis factor signaling.  Cell Death Differ. 2003;  10 45-65
• 12 Plümpe J, Malek N P, Bock C T. et al . NF-kappaB determines between apoptosis and proliferation in hepatocytes during liver regeneration.  Am J Physiol Gastrointest Liver Physiol. 2000;  278 173-183
• 13 Alikhani M, Alikhani Z, Raptis M. et al . TNF-alpha in vivo stimulates apoptosis in fibroblasts through caspase-8 activation and modulates the expression of pro-apoptotic genes.  J Cell Physiol. 2004;  201 341-348
• 14 Reddy P, Slack J L, Davis R. et al . Functional analysis of the domain structure of tumor necrosis factor-alpha converting enzyme.  J Biol Chem. 2000;  275 14608-14614
• 15 Glossop J R, Dawes P T, Nixon N B. et al . Polymorphism in the tumour necrosis factor receptor II gene is associated with circulating levels of soluble tumour necrosis factor receptors in rheumatoid arthritis.  Arthritis Res Ther. 2005;  7 1227-1234
• 16 Himmerich H, Fulda S, Linseisen J. et al . TNF-alpha, soluble TNF receptor and interleukin-6 plasma levels in the general population.  Eur Cytokine Netw. 2006;  17 196-201
• 17 Bastard J P, Maachi M, Lagathu C. et al . Recent advances in the relationship between obesity, inflammation, and insulin resistance.  Eur Cytokine Netw. 2006;  17 4-12
• 18 Zeyda M, Farmer D, Todoric J. et al . Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production.  Int J Obes. 2007;  31 1420-1428
• 19 Panagiotakos D B, Pitsavos C, Yannakoulia M. et al . The implication of obesity and central fat on markers of chronic inflammation: The ATTICA study.  Atherosclerosis. 2005;  183 308-315
• 20 Arzt E, Kovalovsky D, Igaz L M. et al . Functional cross-talk among cytokines, T-cell receptor, and glucocorticoid receptor transcriptional activity and action.  Ann N Y Acad Sci. 2000;  917 672-677
• 21 Kapcala L P, Chautard T, Eskay R L. The protective role of the hypothalamic-pituitary-adrenal axis against lethality produced by immune, infectious, and inflammatory stress.  Ann N Y Acad Sci. 1995;  771 419-437
• 22 Silverman M N, Pearce B D, Biron C A. et al . Immune modulation of the hypothalamic-pituitary-adrenal (HPA) axis during viral infection.  Viral Immunol. 2005;  18 41-78
• 23 Tilders F J, DeRijk R H, Van Dam A M. et al . Activation of the hypothalamus-pituitary-adrenal axis by bacterial endotoxins: routes and intermediate signals.  Psychoneuroendocrinology. 1994;  19 209-232
• 24 Besedovsky H O, del Rey A. The cytokine-HPA axis feed-back circuit.  Z Rheumatol. 2000;  59 (Suppl 2) 26-30
• 25 Reul J M, Labeur M S, Wiegers G J. et al . Altered neuroimmunoendocrine communication during a condition of chronically increased brain corticotropin-releasing hormone drive.  Ann N Y Acad Sci. 1998;  840 444-455
• 26 Schöbitz B, Reul J M, Holsboer F. The role of the hypothalamic-pituitary-adrenocortical system during inflammatory conditions.  Crit Rev Neurobiol. 1994;  8 263-291
• 27 Michie H R, Spriggs D R, Manogue K R. et al . Tumor necrosis factor and endotoxin induce similar metabolic responses in human beings.  Surgery. 1988;  104 280-286
• 28 Petrovsky N, McNair P, Harrison L C. Diurnal rhythms of pro-inflammatory cytokines: regulation by plasma cortisol and therapeutic implications.  Cytokine. 1998;  10 307-312
• 29 Conti B, Tabarean I, Andrei C. et al . Cytokines and fever.  Front Biosci. 2004;  9 1433-1449
• 30 Plata-Salamán C R. 1998 Curt P. Richter Award. Brain mechanisms in cytokine-induced anorexia.  Psychoneuroendocrinology. 1999;  24 25-41
• 31 Pessayre D, Berson A, Fromenty B. et al . Mitochondria in steatohepatitis.  Semin Liver Dis. 2001;  21 57-69
• 32 Ledeen R W, Chakraborty G. Cytokines, signal transduction, and inflammatory demyelination: review and hypothesis.  Neurochem Res. 1998;  23 277-289
• 33 Takeuchi H, Jin S, Wang J. et al . Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner.  J Biol Chem. 2006;  281 21362-21368
• 34 Handa S. Concentrations of interleukin-1 beta, interleukin-6, interleukin-8 and TNF-alpha in cerebrospinal fluid from children with septic or aseptic meningitis.  Kurume Med J. 1992;  39 257-265
• 35 Ichiyama T, Hayashi T, Nishikawa M. et al . Cerebrospinal fluid levels of soluble tumour necrosis factor receptor in acute encephalitis.  J Neurol. 1996;  243 457-460
• 36 Ichiyama T, Hayashi T, Furukawa S. Cerebrospinal fluid concentrations of soluble tumor necrosis factor receptor in bacterial and aseptic meningitis.  Neurology. 1996;  46 837-838
• 37 Mukai A O, Krebs V L, Bertoli C J. et al . TNF-alpha and IL-6 in the diagnosis of bacterial and aseptic meningitis in children.  Pediatr Neurol. 2006;  34 25-29
• 38 Dulkerian S J, Kilpatrick L, Costarino A T. et al . Cytokine elevations in infants with bacterial and aseptic meningitis.  J Pediatr. 1995;  126 872-876
• 39 Bociaga-Jasik M, Garlicki A, Kalinowska-Nowak A. et al . Concentration of proinflammatory cytokines (TNF-alpha, IL-8) in the cerebrospinal fluid and the course of bacterial meningitis.  Przegl Lek. 2004;  61 78-85
• 40 Fida N M, Al-Mughales J, Farouq M. Interleukin-1alpha, interleukin-6 and tumor necrosis factor-alpha levels in children with sepsis and meningitis.  Pediatr Int. 2006;  48 118-124
• 41 Babulas V, Factor-Litvak P, Goetz R. et al . Prenatal exposure to maternal genital and reproductive infections and adult schizophrenia.  Am J Psychiatry. 2006;  163 927-929
• 42 Ravi V, Parida S, Desai A. et al . Correlation of tumor necrosis factor levels in the serum and cerebrospinal fluid with clinical outcome in Japanese encephalitis patients.  J Med Virol. 1997;  51 132-136
• 43 Sergerie Y, Rivest S, Boivin G. Tumor necrosis factor-alpha and interleukin-1 beta play a critical role in the resistance against lethal herpes simplex virus encephalitis.  J Infect Dis. 2007;  196 853-860
• 44 Mrak R E, Griffin W S. Potential inflammatory biomarkers in Alzheimer’s disease.  J Alzheimers Dis. 2005;  8 369-375
• 45 Mrak R E, Griffin W S. Common inflammatory mechanisms in Lewy body disease and Alzheimer disease.  J Neuropathol Exp Neurol. 2007;  66 683-686
• 46 Griffin W S, Liu L, Li Y. et al . Interleukin-1 mediates Alzheimer and Lewy body pathologies.  J Neuroinflammation. 2006;  3 5
• 47 Lemere C A. A beneficial role for IL-1 beta in Alzheimer disease?.  J Clin Invest. 2007;  117 1483-1485
• 48 Shaftel S S, Griffin W S, O’Banion M K. The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective.  J Neuroinflammation. 2008;  5 7
• 49 Rogers J T, Lahiri D K. Metal and inflammatory targets for Alzheimer’s disease.  Curr Drug Targets. 2004;  5 535-551
• 50 Baranowska-Bik A, Bik W, Wolinska-Witort E. et al . Plasma beta amyloid and cytokine profile in women with Alzheimer’s disease.  Neuro Endocrinol Lett. 2008;  29 75-79
• 51 Bonotis K, Krikki E, Holeva V. et al . Systemic immune aberrations in Alzheimer’s disease patients.  J Neuroimmunol. 2008;  193 183-187
• 52 Guerreiro R J, Santana I, Brás J M. et al . Peripheral inflammatory cytokines as biomarkers in Alzheimer’s disease and mild cognitive impairment.  Neurodegener Dis. 2007;  4 406-412
• 53 Griffin W S. Perispinal etanercept: potential as an Alzheimer therapeutic.  J Neuroinflammation. 2008;  5 3
• 54 He P, Zhong Z, Lindholm K. et al . Deletion of tumor necrosis factor death receptor inhibits amyloid beta generation and prevents learning and memory deficits in Alzheimer’s mice.  J Cell Biol. 2007;  178 829-841
• 55 Medeiros R, Prediger R D, Passos G F. et al . Connecting TNF-alpha signaling pathways to iNOS expression in a mouse model of Alzheimer’s disease: relevance for the behavioral and synaptic deficits induced by amyloid beta protein.  J Neurosci. 2007;  27 5394-5404
• 56 Kim Y S, Joh T H. Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson’s disease.  Exp Mol Med. 2006;  38 333-347
• 57 Tansey M G, McCoy M K, Frank-Cannon T C. Neuroinflammatory mechanisms in Parkinson’s disease: potential environmental triggers, pathways, and targets for early therapeutic intervention.  Exp Neurol. 2007;  208 1-25
• 58 Nagatsu T, Sawada M. Inflammatory process in Parkinson’s disease: role for cytokines.  Curr Pharm Des. 2005;  11 999-1016
• 59 Sawada M, Imamura K, Nagatsu T. Role of cytokines in inflammatory process in Parkinson’s disease.  J Neural Transm Suppl. 2006;  70 373-381
• 60 Mogi M, Harada M, Riederer P. et al . Tumor necrosis factor-alpha (TNF-alpha) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients.  Neurosci Lett. 1994;  165 208-210
• 61 Hirsch E C, Hunot S, Damier P. et al . Glial cells and inflammation in Parkinson’s disease: a role in neurodegeneration?.  Ann Neurol. 1998;  44 115-120
• 62 Wu Y R, Feng I H, Lyu R K. et al . Tumor necrosis factor-alpha promoter polymorphism is associated with the risk of Parkinson’s disease.  Am J Med Genet B Neuropsychiatr Genet. 2007;  144B 300-304
• 63 Nishimura M, Mizuta I, Mizuta E. et al . Influence of interleukin-1beta gene polymorphisms on age-at-onset of sporadic Parkinson’s disease.  Neurosci Lett. 2000;  284 73-76
• 64 McCoy M K, Martinez T N, Ruhn K A. et al . Blocking soluble tumor necrosis factor signaling with dominant-negative tumor necrosis factor inhibitor attenuates loss of dopaminergic neurons in models of Parkinson’s disease.  J Neurosci. 2006;  26 9365-9375
• 65 Wu D C, Jackson-Lewis V, Vila M. et al . Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease.  J Neurosci. 2002;  22 1763-1771
• 66 Welsh P, Lowe G D, Chalmers J. et al . Associations of proinflammatory cytokines with the risk of recurrent stroke.  Stroke. 2008;  39 2226-2230
• 67 Hoshi T, Kitagawa K, Yamagami H. et al . Relations of serum high-sensitivity C-reactive protein and interleukin-6 levels with silent brain infarction.  Stroke. 2005;  36 768-772
• 68 Rubattu S, Speranza R, Ferrari M. et al . A role of TNF-alpha gene variant on juvenile ischemic stroke: a case-control study.  Eur J Neurol. 2005;  12 989-993
• 69 Waje-Andreassen U, Kråkenes J, Ulvestad E. et al . IL-6: an early marker for outcome in acute ischemic stroke.  Acta Neurol Scand. 2005;  111 360-365
• 70 Rodríguez-Yáñez M, Castillo J. Role of inflammatory markers in brain ischemia.  Curr Opin Neurol. 2008;  21 353-357
• 71 Jenny N S, Tracy R P, Ogg M S. et al . In the elderly, interleukin-6 plasma levels and the −174G>C polymorphism are associated with the development of cardiovascular disease.  Arterioscler Thromb Vasc Biol. 2002;  22 2066-2071
• 72 Ridker P M, Rifai N, Stampfer M J. et al . Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men.  Circulation. 2000;  101 1767-1772
• 73 Harris T B, Ferrucci L, Tracy R P. et al . Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly.  Am J Med. 1999;  106 506-512
• 74 Park H S, Park J Y, Yu R. Relationship of obesity and visceral adiposity with serum concentrations of CRP, TNF-alpha and IL-6.  Diabetes Res Clin Pract. 2005;  69 29-35
• 75 Adamopoulos S, Parissis J, Karatzas D. et al . Physical training modulates proinflammatory cytokines and the soluble Fas/soluble Fas ligand system in patients with chronic heart failure.  J Am Coll Cardiol. 2002;  39 653-663
• 76 Tanabe A, Nomura S. Pathophysiology of depression.  Nippon Rinsho. 2007;  65 1585-1590
• 77 Haack M, Hinze-Selch D, Fenzel T. et al . Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and diagnosis.  J Psychiatr Res. 1999;  33 407-418
• 78 Maes M, Song C, Lin A H. et al . Negative immunoregulatory effects of antidepressants: inhibition of interferon-gamma and stimulation of interleukin-10 secretion.  Neuropsychopharmacology. 1999;  20 370-379
• 79 Pucak M L, Kaplin A I. Unkind cytokines: current evidence for the potential role of cytokines in immune-mediated depression.  Int Rev Psychiatry. 2005;  17 477-483
• 80 Maes M, Scharpé S, Meltzer H Y. et al . Relationships between interleukin-6 activity, acute phase proteins, and function of the hypothalamic-pituitary-adrenal axis in severe depression.  Psychiatry Res. 1993;  49 11-27
• 81 O’Brien S M, Scott L V, Dinan T G. Cytokines: abnormalities in major depression and implications for pharmacological treatment.  Hum Psychopharmacol. 2004;  19 397-403
• 82 Reichenberg A, Yirmiya R, Schuld A. et al . Cytokine-associated emotional and cognitive disturbances in humans.  Arch Gen Psychiatry. 2001;  58 445-452
• 83 Reichenberg A, Kraus T, Haack M. et al . Endotoxin-induced changes in food consumption in healthy volunteers are associated with TNF-alpha and IL-6 secretion.  Psychoneuroendocrinology. 2002;  27 945-956
• 84 Linthorst A C, Reul J M. Inflammation and brain function under basal conditions and during long-term elevation of brain corticotropin-releasing hormone levels.  Adv Exp Med Biol. 1999;  461 129-152
• 85 Yirmiya R. Behavioral and psychological effects of immune activation: implications for depression due to a general medical condition.  Curr Opin Psychiatry. 1997;  10 470-476
• 86 Schuld A, Schmid D A, Haack M. et al . Hypothalamo-pituitary-adrenal function in patients with depressive disorders is correlated with baseline cytokine levels, but not with cytokine responses to hydrocortisone.  J Psychiatr Res. 2003;  37 463-470
• 87 Himmerich H, Binder E B, Künzel H E. et al . Successful antidepressant therapy restores the disturbed interplay between TNF-alpha system and HPA axis.  Biol Psychiatry. 2006;  60 882-888
• 88 Zhu C B, Blakely R D, Hewlett W A. The proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters.  Neuropsychopharmacology. 2006;  31 2121-2131
• 89 Wichers M, Maes M. The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans.  Int J Neuropsychopharmacol. 2002;  5 375-388
• 90 Brown A S, Hooton J, Schaefer C A. et al . Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring.  Am J Psychiatry. 2004;  161 889-895
• 91 Brown A S, Begg M D, Gravenstein S. et al . Serologic evidence of prenatal influenza in the etiology of schizophrenia.  Arch Gen Psychiatry. 2004;  61 774-780
• 92 Brown A S, Schaefer C A, Quesenberry C P. et al . Maternal exposure to toxoplasmosis and risk of schizophrenia in adult offspring.  Am J Psychiatry. 2005;  162 767-773
• 93 Buka S L, Cannon T D, Torrey E F. et al . Maternal exposure to herpes simplex virus and risk of psychosis among adult offspring.  Biol Psychiatry. 2008;  63 809-815
• 94 Gattaz W F, Abrahão A L, Foccacia R. Childhood meningitis, brain maturation and the risk of psychosis.  Eur Arch Psychiatry Clin Neurosci. 2004;  254 23-26
• 95 Rantakallio P, Jones P, Moring J. et al . Association between central nervous system infections during childhood and adult onset schizophrenia and other psychoses: a 28-year follow-up.  Int J Epidemiol. 1997;  26 837-843
• 96 Müller N, Riedel M, Ackenheil M. et al . Cellular and humoral immune system in schizophrenia: a conceptual re-evaluation.  World J Biol Psychiatry. 2000;  1 173-179
• 97 Wilke I, Arolt V, Rothermundt M. et al . Investigations of cytokine production in whole blood cultures of paranoid and residual schizophrenic patients.  Eur Arch Psychiatry Clin Neurosci. 1996;  246 279-284
• 98 Kammen, McAllister-Sistilli, Kelley. Relationship between immune and behavioral measures in schizophrenia. Wieselmann, G Current update in psychoimmunology Berlin, Heidelberg, New York; Springer 1997
• 99 Müller N, Schwarz M J. Immunologische Aspekte bei schizophrenen Störungen.  Nervenarzt. 2007;  78 253-263
• 100 Stone T W. Neuropharmacology of quinolinic and kynurenic acids.  Pharmacol Rev. 1993;  45 309-379
• 101 Erhardt S, Schwieler L, Engberg G. Kynurenic acid and schizophrenia.  Adv Exp Med Biol. 2003;  527 155-165
• 102 Erhardt S, Schwieler L, Nilsson L. et al . The kynurenic acid hypothesis of schizophrenia.  Physiol Behav. 2007;  92 203-209
• 103 Schwarcz R, Rassoulpour A, Wu H Q. et al . Increased cortical kynurenate content in schizophrenia.  Biol Psychiatry. 2001;  50 521-530
• 104 Müller N, Ulmschneider M, Scheppach C. et al . COX-2 inhibition as a treatment approach in schizophrenia: immunological considerations and clinical effects of celecoxib add-on therapy.  Eur Arch Psychiatry Clin Neurosci. 2004;  254 14-22
• 105 Müller N, Riedel M, Schwarz M J. Psychotropic effects of COX-2 inhibitors--a possible new approach for the treatment of psychiatric disorders.  Pharmacopsychiatry. 2004;  37 266-269
• 106 Müller N, Riedel M, Scheppach C. et al . Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia.  Am J Psychiatry. 2002;  159 1029-1034
• 107 Müller N, Riedel M, Schwarz M J. et al . Clinical effects of COX-2 inhibitors on cognition in schizophrenia.  Eur Arch Psychiatry Clin Neurosci. 2005;  255 149-151
• 108 Yokota O, Terada S, Ishihara T. et al . Neuronal expression of cyclooxygenase-2, a pro-inflammatory protein, in the hippocampus of patients with schizophrenia.  Prog Neuropsychopharmacol Biol Psychiatry. 2004;  28 715-721
• 109 Kato T, Monji A, Hashioka S. et al . Risperidone significantly inhibits interferon-gamma-induced microglial activation in vitro.  Schizophr Res. 2007;  92 108-115
• 110 Potvin S, Stip E, Sepehry A A. et al . Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review.  Biol Psychiatry. 2008;  63 801-808
• 111 Bresee C J, Delrahim K, Maddux R E. et al . The effects of celecoxib augmentation on cytokine levels in schizophrenia.  Int J Neuropsychopharmacol. 2006;  9 343-348
• 112 Mayer G, Pollmächer T. Narkolepsie – Neue Chancen in Diagnostik und Therapie. Thieme 2007
• 113 Lin L, Hungs M, Mignot E. Narcolepsy and the HLA region.  J Neuroimmunol. 2001;  117 9-20
• 114 Mignot E, Tafti M, Dement W C. et al . Narcolepsy and immunity.  Adv Neuroimmunol. 1995;  5 23-37
• 115 Möller E, Böhme J, Valugerdi M A. et al . Speculations on mechanisms of HLA associations with autoimmune diseases and the specificity of „autoreactive” T lymphocytes.  Immunol Rev. 1990;  118 5-19
• 116 Dauvilliers Y. Neurodegenerative, autoimmune and genetic processes of human and animal narcolepsy.  Rev Neurol. 2003;  159 83-87
• 117 Thannickal T C, Moore R Y, Nienhuis R. et al . Reduced number of hypocretin neurons in human narcolepsy.  Neuron. 2000;  27 469-474
• 118 Hohjoh H, Nakayama T, Ohashi J. et al . Significant association of a single nucleotide polymorphism in the tumor necrosis factor-alpha (TNF-alpha) gene promoter with human narcolepsy.  Tissue Antigens. 1999;  54 138-145
• 119 Himmerich H, Beitinger P A, Fulda S. et al . Plasma levels of tumor necrosis factor alpha and soluble tumor necrosis factor receptors in patients with narcolepsy.  Arch Intern Med. 2006;  166 1739-1743
• 120 Hinze-Selch D, Schuld A, Kraus T. et al . Effects of antidepressants on weight and on the plasma levels of leptin, TNF-alpha and soluble TNF receptors: A longitudinal study in patients treated with amitriptyline or paroxetine.  Neuropsychopharmacology. 2000;  23 13-19
• 121 Kraus T, Haack M, Schuld A. et al . Body weight, the tumor necrosis factor system, and leptin production during treatment with mirtazapine or venlafaxine.  Pharmacopsychiatry. 2002;  35 220-225
• 122 Pollmächer T, Hinze-Selch D, Mullington J. Effects of clozapine on plasma cytokine and soluble cytokine receptor levels.  J Clin Psychopharmacol. 1996;  16 403-409
• 123 Schuld A, Kraus T, Haack M. et al . Plasma levels of cytokines and soluble cytokine receptors during treatment with olanzapine.  Schizophr Res. 2000;  43 164-166
• 124 Maes M, Song C, Lin A H. et al . In vitro immunoregulatory effects of lithium in healthy volunteers.  Psychopharmacology. 1999;  143 401-407
• 125 Himmerich H, Koethe D, Schuld A. et al . Plasma levels of leptin and endogenous immune modulators during treatment with carbamazepine or lithium.  Psychopharmacology. 2005;  179 447-451
• 126 Kraus T, Haack M, Schuld A. et al . Body weight and leptin plasma levels during treatment with antipsychotic drugs.  Am J Psychiatry. 1999;  156 312-314
• 127 Pollmächer T, Hinze-Selch D, Fenzel T. et al . Plasma levels of cytokines and soluble cytokine receptors during treatment with haloperidol.  Am J Psychiatry. 1997;  154 1763-1765
• 128 Brustolim D, Ribeiro-dos-Santos R, Kast R E. et al . A new chapter opens in anti-inflammatory treatments: the antidepressant bupropion lowers production of tumor necrosis factor-alpha and interferon-gamma in mice.  Int Immunopharmacol. 2006;  6 903-907
• 129 Himmerich H, Schuld A, Haack M. et al . Early prediction of changes in weight during six weeks of treatment with antidepressants.  J Psychiatr Res. 2004;  38 485-489
• 130 Davis M. Hepatotoxicity of antidepressants.  Int Clin Psychopharmacol. 1991;  6 97-103
• 131 Selim K, Kaplowitz N. Hepatotoxicity of psychotropic drugs.  Hepatology. 1999;  29 1347-1351
• 132 Himmerich H, Kaufmann C, Schuld A. et al . Elevation of liver enzyme levels during psychopharmacological treatment is associated with weight gain.  J Psychiatr Res. 2005;  39 35-42
• 133 Choi I, Kang H S, Yang Y. et al . IL-6 induces hepatic inflammation and collagen synthesis in vivo.  Clin Exp Immunol. 1994;  95 530-535
• 134 Ikejima K, Takei Y, Honda H. et al . Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat.  Gastroenterology. 2002;  122 1399-1410
• 135 Tilg H. Cytokines and liver diseases.  Can J Gastroenterol. 2001;  15 661-668
• 136 Müller N, Schwarz M. Schizophrenia as an inflammation-mediated dysbalance of glutamatergic neurotransmission.  Neurotox Res. 2006;  10 131-148
• 137 Pollmächer T, Schuld A, Kraus T. et al . Zur klinischen Relevanz der Wirkung von Clozapin auf die Freisetzung von Zytokinen und löslichen Zytokinrezeptoren.  Fortschr Neurol Psychiatr. 2001;  69 (Suppl 2) 65-74
• 138 Tyring S, Gottlieb A, Papp K. et al . Etanercept and clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised phase III trial.  Lancet. 2006;  367 29-35
• 139 Uguz F, Akman C, Kucuksarac S. et al . Anti-tumor necrosis factor-alpha therapy is associated with less frequent mood and anxiety disorders in patients with rheumatoid arthritis.  Psychiatry Clin Neurosci. 2009;  63 50-55
• 140 Ricart E, García-Bosch O, Ordás I. et al . Are we giving biologics too late? The case for early versus late use.  World J Gastroenterol. 2008;  14 5523-5527
• 141 Bongartz T, Sutton A J, Sweeting M J. et al . Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials.  JAMA. 2006;  295 2275-2285
• 142 Nasir A, Greenberg J D. TNF antagonist safety in rheumatoid arthritis: updated evidence from observational registries.  Bull NYU Hosp Jt Dis. 2007;  65 178-181
• 143 Solomon D H, Karlson E W, Rimm E B. et al . Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis.  Circulation. 2003;  107 1303-1307
• 144 Wolfe F, Freundlich B, Straus W L. Increase in cardiovascular and cerebrovascular disease prevalence in rheumatoid arthritis.  J Rheumatol. 2003;  30 36-40
• 145 Efimov G A, Kruglov A A, Tillib S V. et al . Tumor Necrosis Factor and the consequences of its ablation in vivo.  Mol Immunol. 2009;  Epub 19.2.2009
• 146 Sperner-Unterweger B. Biologische Hypothesen zur Schizophrenie: Mögliche Einflüsse von Immunologie und Endokrinologie.  Fortschr Neurol Psychiatr. 2005;  73 (Suppl 1) 38-43
• 147 Fromont A, De Seze J, Fleury M C. et al . Inflammatory demyelinating events following treatment with anti-tumor necrosis factor.  Cytokine. 2009;  45 55-57