Physical activity and exercise attenuate neuroinflammation in neurological diseases

Brain Research Bulletin

Volumn 125, Issue , 2016, Pages 19-29

  Spielman, Lindsay Joy ^a   Little, Jonathan Peter ^a   Klegeris, Andis ^a  

^a UNIVERSITY OF BRITISH COLUMBIA   (Canada)

Author keywords

Alzheimer's disease; Exercise; Major depressive disorder; Parkinson's disease; Schizophrenia; Sedentary lifestyle

Indexed keywords

ALZHEIMER DISEASE; EXERCISE; HUMAN; IMMUNOMODULATION; MAJOR DEPRESSION; NERVOUS SYSTEM INFLAMMATION; NEUROLOGIC DISEASE; NONHUMAN; PARKINSON DISEASE; PHYSICAL ACTIVITY; PRIORITY JOURNAL; REVIEW; SCHIZOPHRENIA; ANIMAL; COMPLICATION; ENCEPHALITIS; GLIA; MENTAL DISEASE; METABOLISM; PATHOLOGY; PHYSIOLOGY; SEDENTARY LIFESTYLE;

CYTOKINE;

ANIMALS; CYTOKINES; ENCEPHALITIS; EXERCISE; HUMANS; MENTAL DISORDERS; NERVOUS SYSTEM DISEASES; NEUROGLIA; SEDENTARY LIFESTYLE;

EID: 84961910974     PISSN: 03619230     EISSN: 18732747     Source Type: Journal    
DOI: 10.1016/j.brainresbull.2016.03.012     Document Type: Review

References (195)

1. Adamson B.C., Ensari I., Motl R.W. Effect of exercise on depressive symptoms in adults with neurologic disorders: a systematic review and meta-analysis. Arch. Phys. Med. Rehabil. 2015, 96(7):1329-1338.
2. Agudelo L.Z., Femenia T., Orhan F., Porsmyr-Palmertz M., Goiny M., Martinez-Redondo V., Correia J.C., Izadi M., Bhat M., Schuppe-Koistinen I., et al. Skeletal muscle PGC-1alpha1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. Cell 2014, 159(1):33-45.
3. Altshuler L.L., Abulseoud O.A., Foland-Ross L., Bartzokis G., Chang S., Mintz J., Hellemann G., Vinters H.V. Amygdala astrocyte reduction in subjects with major depressive disorder but not bipolar disorder. Bipolar Disord. 2010, 12(5):541-549.
4. Annesi J.J., Tennant G.A. Exercise program-induced mood improvement and improved eating in severely obese adults. Int. Q. Community Health Educ. 2012, 33(4):391-402.
5. Archer T., Kostrzewa R.M. Physical exercise alleviates health defects, symptoms, and biomarkers in schizophrenia spectrum disorder. Neurotox. Res. 2015, 28(3):268-280.
6. Arciniegas D.B. Psychosis. Continuum 2015, 21(3):715-736.
7. Banati R.B., Daniel S.E., Blunt S.B. Glial pathology but absence of apoptotic nigral neurons in long-standing Parkinson's disease. Mov. Disord. 1998, 13(2):221-227.
8. Banks W.A., Kastin A.J., Broadwell R.D. Passage of cytokines across the blood-brain barrier. Neuroimmunomodulation 1995, 2(4):241-248.
9. Barnes D.E., Yaffe K. The projected effect of risk factor reduction on Alzheimer's disease prevalence. Lancet Neurol. 2011, 10(9):819-828.
10. Belarbi K., Burnouf S., Fernandez-Gomez F.J., Laurent C., Lestavel S., Figeac M., Sultan A., Troquier L., Leboucher A., Caillierez R., et al. Beneficial effects of exercise in a transgenic mouse model of Alzheimer's disease-like Tau pathology. Neurobiol. Dis. 2011, 43(2):486-494.
11. Bennett M.R. Synapse regression in depression: the role of 5-HT receptors in modulating NMDA receptor function and synaptic plasticity. Aust. N. Z. J. Psychiatry 2010, 44(4):301-308.
12. Bergman D. The endocrinology of exercise. Intern. Emerg. Med. 2013, 8(Suppl. 1):S17-21.
13. Blackburn S.D., Wherry E.J. IL-10, T cell exhaustion and viral persistence. Trends Microbiol. 2007, 15(4):143-146.
14. Blier P., Keller M.B., Pollack M.H., Thase M.E., Zajecka J.M., Dunner D.L. Preventing recurrent depression: long-term treatment for major depressive disorder. J. Clin. Psychiatry 2007, 68(3):e06.
15. Block M.L., Hong J.S. Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog. Neurobiol. 2005, 76(2):77-98.
16. Block M.L., Zecca L., Hong J.S. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat. Rev. Neurosci. 2007, 8(1):57-69.
17. Bloem B.R., de Vries N.M., Ebersbach G. Nonpharmacological treatments for patients with Parkinson's disease. Mov. Disord. 2015, 30(11):1504-1520.
18. Blumenthal J.A., Babyak M.A., Doraiswamy P.M., Watkins L., Hoffman B.M., Barbour K.A., Herman S., Craighead W.E., Brosse A.L., Waugh R., et al. Exercise and pharmacotherapy in the treatment of major depressive disorder. Psychosom. Med. 2007, 69(7):587-596.
19. Brett F.M., Mizisin A.P., Powell H.C., Campbell I.L. Evolution of neuropathologic abnormalities associated with blood-brain barrier breakdown in transgenic mice expressing interleukin-6 in astrocytes. J. Neuropathol. Exp. Neurol. 1995, 54(6):766-775.
20. Brundage S.I., Kirilcuk N.N., Lam J.C., Spain D.A., Zautke N.A. Insulin increases the release of proinflammatory mediators. J. Trauma 2008, 65(2):367-372.
21. Bruun J.M., Helge J.W., Richelsen B., Stallknecht B. Diet and exercise reduce low-grade inflammation and macrophage infiltration in adipose tissue but not in skeletal muscle in severely obese subjects. Am. J. Physiol. Endocrinol. Metab. 2006, 290(5):E961-967.
22. Calabrese F., Rossetti A.C., Racagni G., Gass P., Riva M.A., Molteni R. Brain-derived neurotrophic factor: a bridge between inflammation and neuroplasticity. Front. Cell. Neurosci. 2014, 8:430.
23. Cameron B., Landreth G.E. Inflammation, microglia, and Alzheimer's disease. Neurobiol. Dis. 2010, 37(3):503-509.
24. Canning C.G., Sherrington C., Lord S.R., Close J.C., Heritier S., Heller G.Z., Howard K., Allen N.E., Latt M.D., Murray S.M., et al. Exercise for falls prevention in Parkinson disease: a randomized controlled trial. Neurology 2015, 84(3):304-312.
25. Carek P.J., Laibstain S.E., Carek S.M. Exercise for the treatment of depression and anxiety. Int. J. Psychiatry Med. 2011, 41(1):15-28.
26. Carlsson A., Lindqvist M. Effect of chlorpromazine or haloperidol on formation of 3methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol. Toxicol. (Copenh) 1963, 20:140-144.
27. Centers for Disease Control and Prevention. (2015). Division of nutrition, physical activity, and Oobesity. Accessed: 16.02.24 . http://www.cdc.gov/physicalactivity/basics/glossary/.
28. Colton C.A., Mott R.T., Sharpe H., Xu Q., Van Nostrand W.E., Vitek M.P. Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD. J. Neuroinflammation 2006, 3:27.
29. Comassi M., Vitolo E., Pratali L., Del Turco S., Dellanoce C., Rossi C., Santini E., Solini A. Acute effects of different degrees of ultra-endurance exercise on systemic inflammatory responses. Intern. Med. J. 2015, 45(1):74-79.
30. Cotter D., Mackay D., Landau S., Kerwin R., Everall I. Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder. Arch. Gen. Psychiatry 2001, 58(6):545-553.
31. Cunningham C. Microglia and neurodegeneration: the role of systemic inflammation. Glia 2013, 61(1):71-90.
32. Czlonkowska A., Kurkowska-Jastrzebska I., Czlonkowski A., Peter D., Stefano G.B. Immune processes in the pathogenesis of Parkinson's disease-a potential role for microglia and nitric oxide. Med. Sci. Monit. 2002, 8(8):RA165-177.
33. Dantzer R., O'Connor J.C., Lawson M.A., Kelley K.W. Inflammation-associated depression: from serotonin to kynurenine. Psychoneuroendocrinology 2011, 36(3):426-436.
34. Dayan P., Huys Q.J. Serotonin, inhibition, and negative mood. PLoS Comput. Biol. 2008, 4(2):e4.
35. Dheen S.T., Kaur C., Ling E.A. Microglial activation and its implications in the brain diseases. Curr. Med. Chem. 2007, 14(11):1189-1197.
36. Dilger R.N., Johnson R.W. Aging, microglial cell priming, and the discordant central inflammatory response to signals from the peripheral immune system. J. Leukoc. Biol. 2008, 84(4):932-939.
37. Doose M., Ziegenbein P.D., Hoos O., Reim D., Stengert W., Hoffer N., Vogel C., Ziert Y., Sieberer M. Self-selected intensity exercise in the treatment of major depression: a pragmatic RCT. Int. J. Psychiatry Clin. Pract. 2015, 19(4):266-275.
38. Dowlati Y., Herrmann N., Swardfager W., Liu H., Sham L., Reim E.K., Lanctot K.L. A meta-analysis of cytokines in major depression. Biol. Psychiatry 2010, 67(5):446-457.
39. Dunn A.L., Trivedi M.H., Kampert J.B., Clark C.G., Chambliss H.O. Exercise treatment for depression: efficacy and dose response. Am. J. Prev. Med. 2005, 28(1):1-8.
40. Egan B., Zierath J.R. Exercise metabolism and the molecular regulation of skeletal muscle adaptation. Cell Metab. 2013, 17(2):162-184.
41. Erickson K.I., Miller D.L., Roecklein K.A. The aging hippocampus: interactions between exercise, depression, and BDNF. Neuroscientist 2012, 18(1):82-97.
42. Eyre H., Baune B.T. Neuroimmunological effects of physical exercise in depression. Brain Behav. Immun. 2012, 26(2):251-266.
43. Falconer C.L., Cooper A.R., Walhin J.P., Thompson D., Page A.S., Peters T.J., Montgomery A.A., Sharp D.J., Dayan C.M., Andrews R.C. Sedentary time and markers of inflammation in people with newly diagnosed type 2 diabetes. Nutr. Metab. Cardiovasc. Dis. 2014, 24(9):956-962.
44. Fattori E., Lazzaro D., Musiani P., Modesti A., Alonzi T., Ciliberto G. IL-6 expression in neurons of transgenic mice causes reactive astrocytosis and increase in ramified microglial cells but no neuronal damage. Eur. J. Neurosci. 1995, 7(12):2441-2449.
45. Fillman S.G., Cloonan N., Miller L.C., Weickert C.S. Markers of inflammation in the prefrontal cortex of individuals with schizophrenia. Mol. Psychiatry 2013, 18(2):133.
46. Fiuza-Luces C., Garatachea N., Berger N.A., Lucia A. Exercise is the real polypill. Physiology (Bethesda) 2013, 28(5):330-358.
47. Flynn M.G., McFarlin B.K. Toll-like receptor 4: link to the anti-inflammatory effects of exercise?. Exerc. Sport. Sci. Rev. 2006, 34(4):176-181.
48. Frank-Cannon T.C., Alto L.T., McAlpine F.E., Tansey M.G. Does neuroinflammation fan the flame in neurodegenerative diseases?. Mol. Neurodegener. 2009, 4:47.
49. Frazzitta G., Maestri R., Ghilardi M.F., Riboldazzi G., Perini M., Bertotti G., Boveri N., Buttini S., Lombino F.L., Uccellini D., et al. Intensive rehabilitation increases BDNF serum levels in parkinsonian patients: a randomized study. Neurorehabil. Neural Repair 2014, 28(2):163-168.
50. Frazzitta G., Maestri R., Bertotti G., Riboldazzi G., Boveri N., Perini M., Uccellini D., Turla M., Comi C., Pezzoli G., et al. Intensive rehabilitation treatment in early Parkinson's disease: a randomized pilot study with a 2-year follow-up. Neurorehabil. Neural Repair 2015, 29(2):123-131.
51. Funk J.A., Gohlke J., Kraft A.D., McPherson C.A., Collins J.B., Jean Harry G. Voluntary exercise protects hippocampal neurons from trimethyltin injury: possible role of interleukin-6 to modulate tumor necrosis factor receptor-mediated neurotoxicity. Brain Behav. Immun. 2011, 25(6):1063-1077.
52. Gaesser G.A. Exercise for prevention and treatment of cardiovascular disease, type 2 diabetes, and metabolic syndrome. Curr. Diab. Rep. 2007, 7(1):14-19.
53. Garland T., Schutz H., Chappell M.A., Keeney B.K., Meek T.H., Copes L.E., Acosta W., Drenowatz C., Maciel R.C., van Dijk G., et al. The biological control of voluntary exercise, spontaneous physical activity and daily energy expenditure in relation to obesity: human and rodent perspectives. J. Exp. Biol. 2011, 214(Pt 2):206-229.
54. Giallauria F., Gentile M., Chiodini P., Berrino F., Mattiello A., Maresca L., Vitelli A., Mancini M., Grieco A., Lucci R., et al. Exercise training reduces high mobility group box-1 protein levels in women with breast cancer: findings from the DIANA-5 study. Monaldi Arch. Chest Dis. 2014, 82(2):61-67.
55. Gibbons T.E., Pence B.D., Petr G., Ossyra J.M., Mach H.C., Bhattacharya T.K., Perez S., Martin S.A., McCusker R.H., Kelley K.W., et al. Voluntary wheel running, but not a diet containing (-)-epigallocatechin-3-gallate and beta-alanine improves learning, memory and hippocampal neurogenesis in aged mice. Behav. Brain Res. 2014, 272:131-140.
56. Giralt M., Penkowa M., Hernandez J., Molinero A., Carrasco J., Lago N., Camats J., Campbell I.L., Hidalgo J. Metallothionein-1+2 deficiency increases brain pathology in transgenic mice with astrocyte-targeted expression of interleukin 6. Neurobiol. Dis. 2002, 9(3):319-338.
57. Gleeson M., Bishop N.C., Stensel D.J., Lindley M.R., Mastana S.S., Nimmo M.A. The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat. Rev. Immunol. 2011, 11(9):607-615.
58. Gleeson M., Bishop N., Oliveira M., McCauley T., Tauler P., Muhamad A.S. Respiratory infection risk in athletes: association with antigen-stimulated IL-10 production and salivary IgA secretion. Scand. J. Med. Sci. Sports 2012, 22(3):410-417.
59. Gong C.Y., Li Z., Wang H.M., Liu J., Chen L., Zhang H.W., Wang X., Yang J. Targeting the kynurenine pathway as a potential strategy to prevent and treat Alzheimer's disease. Med. Hypotheses 2011, 77(3):383-385.
60. Guan Z., Fang J. Peripheral immune activation by lipopolysaccharide decreases neurotrophins in the cortex and hippocampus in rats. Brain Behav. Immun. 2006, 20(1):64-71.
61. Gyorkos A.M., McCullough M.J., Spitsbergen J.M. Glial cell line-derived neurotrophic factor (GDNF) expression and NMJ plasticity in skeletal muscle following endurance exercise. Neurosci. Biobehav. Rev. 2014, 257:111-118.
62. Harizi H., Corcuff J.B., Gualde N. Arachidonic-acid-derived eicosanoids: roles in biology and immunopathology. Trends Mol. Med. 2008, 14(10):461-469.
63. Hauw J.J., Verny M., Delaere P., Cervera P., He Y., Duyckaerts C. Constant neurofibrillary changes in the neocortex in progressive supranuclear palsy. Basic differences with Alzheimer's disease and aging. Neurosci. Lett. 1990, 119(2):182-186.
64. Hoffman J.M., Bell K.R., Powell J.M., Behr J., Dunn E.C., Dikmen S., Bombardier C.H. A randomized controlled trial of exercise to improve mood after traumatic brain injury. Phys. Med. Rehabil. 2010, 2(10):911-919.
65. Holloszy J.O. Exercise-induced increase in muscle insulin sensitivity. J. Appl. Physiol. (1985) 2005, 99(1):338-343.
66. Howes O.D., Kapur S. The dopamine hypothesis of schizophrenia: version III-the final common pathway. Schizophr. Bull. 2009, 35(3):549-562.
67. Iida K.T., Shimano H., Kawakami Y., Sone H., Toyoshima H., Suzuki S., Asano T., Okuda Y., Yamada N. Insulin up-regulates tumor necrosis factor-alpha production in macrophages through an extracellular-regulated kinase-dependent pathway. J. Biol. Chem. 2001, 276(35):32531-32537.
68. Javitt D.C. Glutamate and schizophrenia phencyclidine, N-methyl-d-aspartate receptors, and dopamine-glutamate interactions. Int. Rev. Neurobiol. 2007, 78:69-108.
69. Jessen K.R. Glial cells. Int. J. Biochem. Cell Biol. 2004, 36(10):1861-1867.
70. Johnson S.S., Castle P.H. How do sleep, food, mood, and exercise relate to well-being?. Am. J. Health Promot. 2015, 29(4):4-5. (TAHP).
71. Kamphuis W., Mamber C., Moeton M., Kooijman L., Sluijs J.A., Jansen A.H., Verveer M., de Groot L.R., Smith V.D., Rangarajan S., et al. GFAP isoforms in adult mouse brain with a focus on neurogenic astrocytes and reactive astrogliosis in mouse models of Alzheimer disease. PLoS One 2012, 7(8):e42823.
72. Kanba S., Kato T. Microglial hypothesis of schizophrenia. Nihon Shinkei Seishin Yakurigaku Zasshi 2014, 34(1):11-13.
73. Kang E.B., Kwon I.S., Koo J.H., Kim E.J., Kim C.H., Lee J., Yang C.H., Lee Y.I., Cho I.H., Cho J.Y. Treadmill exercise represses neuronal cell death and inflammation during Abeta-induced ER stress by regulating unfolded protein response in aged presenilin 2 mutant mice. Apoptosis 2013, 18(11):1332-1347.
74. Kawanishi N., Yano H., Yokogawa Y., Suzuki K. Exercise training inhibits inflammation in adipose tissue via both suppression of macrophage infiltration and acceleration of phenotypic switching from M1 to M2 macrophages in high-fat-diet-induced obese mice. Exerc. Immunol. Rev. 2010, 16:105-118.
75. Kawanishi N., Mizokami T., Yano H., Suzuki K. Exercise attenuates M1 macrophages and CD8+ T cells in the adipose tissue of obese mice. Med. Sci. Sports Exerc. 2013, 45(9):1684-1693.
76. Kegel M.E., Bhat M., Skogh E., Samuelsson M., Lundberg K., Dahl M.L., Sellgren C., Schwieler L., Engberg G., Schuppe-Koistinen I., et al. Imbalanced kynurenine pathway in schizophrenia. Int. J. Tryptophan Res. 2014, 7:15-22.
77. Keller P., Keller C., Carey A.L., Jauffred S., Fischer C.P., Steensberg A., Pedersen B.K. Interleukin-6 production by contracting human skeletal muscle: autocrine regulation by IL-6. Biochem. Biophys. Res. Commun. 2003, 310(2):550-554.
78. Kemi O.J., Loennechen J.P., Wisloff U., Ellingsen O. Intensity-controlled treadmill running in mice: cardiac and skeletal muscle hypertrophy. J. Appl. Physiol. (1985) 2002, 93(4):1301-1309.
79. Kestler L.P., Walker E., Vega E.M. Dopamine receptors in the brains of schizophrenia patients: a meta-analysis of the findings. Behav. Pharmacol. 2001, 12(5):355-371.
80. Kilmartin B., Reen D.J. HSP60 induces self-tolerance to repeated HSP60 stimulation and cross-tolerance to other pro-inflammatory stimuli. Eur. J. Immunol. 2004, 34(7):2041-2051.
81. Kim H.J., Song B.K., So B., Lee O., Song W., Kim Y. Increase of circulating BDNF levels and its relation to improvement of physical fitness following 12 weeks of combined exercise in chronic patients with schizophrenia: a pilot study. Psychiatry Res. 2014, 220(3):792-796.
82. Knab A.M., Bowen R.S., Moore-Harrison T., Hamilton A.T., Turner M.J., Lightfoot J.T. Repeatability of exercise behaviors in mice. Physiol. Behav. 2009, 98(4):433-440.
83. Kohman R.A., DeYoung E.K., Bhattacharya T.K., Peterson L.N., Rhodes J.S. Wheel running attenuates microglia proliferation and increases expression of a proneurogenic phenotype in the hippocampus of aged mice. Brain Behav. Immun. 2012, 26(5):803-810.
84. Kornhuber H.H., Kornhuber J., Kim J.S., Kornhuber M.E. A biochemical theory of schizophrenia. Nervenarzt 1984, 55(11):602-606.
85. Kuo F.C., Lee C.H., Hsieh C.H., Kuo P., Chen Y.C., Hung Y.J. Lifestyle modification and behavior therapy effectively reduce body weight and increase serum level of brain-derived neurotrophic factor in obese non-diabetic patients with schizophrenia. Psychiatry Res. 2013, 209(2):150-154.
86. La Gerche A., Inder W.J., Roberts T.J., Brosnan M.J., Heidbuchel H., Prior D.L. Relationship between inflammatory cytokines and indices of cardiac dysfunction following intense endurance exercise. PLoS One 2015, 10(6):e0130031.
87. Land W.G. The role of damage-associated molecular patterns in human diseases: part I-promoting inflammation and immunity. Sultan Qaboos Univ. Med. J. 2015, 15(1):e9-e21.
88. Lapchak P.A., Araujo D.M., Hefti F. Systemic interleukin-1 beta decreases brain-derived neurotrophic factor messenger RNA expression in the rat hippocampal formation. Neuroscience 1993, 53(2):297-301.
89. Lau Y.S., Patki G., Das-Panja K., Le W.D., Ahmad S.O. Neuroprotective effects and mechanisms of exercise in a chronic mouse model of Parkinson's disease with moderate neurodegeneration. Eur. J. Neurosci. 2011, 33(7):1264-1274.
90. Law L.L., Barnett F., Yau M.K., Gray M.A. Effects of functional tasks exercise on older adults with cognitive impairment at risk of Alzheimer's disease: a randomised controlled trial. Age Ageing 2014, 43(6):813-820.
91. Leem Y.H., Lee Y.I., Son H.J., Lee S.H. Chronic exercise ameliorates the neuroinflammation in mice carrying NSE/htau23. Biochem. Biophys. Res. Commun. 2011, 406(3):359-365.
92. Leza J.C., Garcia-Bueno B., Bioque M., Arango C., Parellada M., Do K., O'Donnell P., Bernardo M. Inflammation in schizophrenia: a question of balance. Neurosci. Biobehav. Rev. 2015, 55:612-626.
93. Liu W., Sheng H., Xu Y., Liu Y., Lu J., Ni X. Swimming exercise ameliorates depression-like behavior in chronically stressed rats: relevant to proinflammatory cytokines and IDO activation. Behav. Brain Res. 2013, 242:110-116.
94. Lull M.E., Block M.L. Microglial activation and chronic neurodegeneration. Neurotherapeutics 2010, 7(4):354-365.
95. Lynch A.M., Murphy K.J., Deighan B.F., O'Reilly J.A., Gun'ko Y.K., Cowley T.R., Gonzalez-Reyes R.E., Lynch M.A. The impact of glial activation in the aging brain. Aging Dis. 2010, 1(3):262-278.
96. Maeda Y., Matsumoto M., Hori O., Kuwabara K., Ogawa S., Yan S.D., Ohtsuki T., Kinoshita T., Kamada T., Stern D.M. Hypoxia/reoxygenation-mediated induction of astrocyte interleukin 6: a paracrine mechanism potentially enhancing neuron survival. J. Exp. Med. 1994, 180(6):2297-2308.
97. Maes M., Kubera M., Obuchowiczwa E., Goehler L., Brzeszcz J. Depression's multiple comorbidities explained by (neuro)inflammatory and oxidative & nitrosative stress pathways. Neuro. Endocrinol. Lett. 2011, 32(1):7-24.
98. Maes M. Evidence for an immune response in major depression: a review and hypothesis. Prog. Neuropsychopharmacol. Biol. Psychiatry 1995, 19(1):11-38.
99. Mahlknecht P., Poewe W. Is there a need to redefine Parkinson's disease?. J. Neural Trans. 2013, 120(Suppl. 1):S9-17.
100. Mandybur T.I. Cerebral amyloid angiopathy and astrocytic gliosis in Alzheimer's disease. Acta Neuropathol. 1989, 78(3):329-331.
101. Marques O., Outeiro T.F. Alpha-synuclein: from secretion to dysfunction and death. Cell Death Dis. 2012, 3:e350.
102. Martin S.A., Dantzer R., Kelley K.W., Woods J.A. Voluntary wheel running does not affect lipopolysaccharide-induced depressive-like behavior in young adult and aged mice. Neuroimmunomodulation 2014, 21(1):52-63.
103. Maynard C.L., Weaver C.T. Diversity in the contribution of interleukin-10 to T-cell-mediated immune regulation. Immunol. Rev. 2008, 226:219-233.
104. McCarthy M. Diet and exercise are effective in preventing type 2 diabetes, task force finds. Brain Med. J. 2015, 351:h3785.
105. McFarlin B.K., Flynn M.G., Campbell W.W., Craig B.A., Robinson J.P., Stewart L.K., Timmerman K.L., Coen P.M. Physical activity status, but not age, influences inflammatory biomarkers and toll-like receptor 4. J. Gerontol. A. Biol. Sci. Med. Sci. 2006, 61(4):388-393.
106. Melancon M.O., Lorrain D., Dionne I.J. Changes in markers of brain serotonin activity in response to chronic exercise in senior men. Appl. Physiol. Nutr. Metab. 2014, 39(11):1250-1256.
107. Michigan A., Johnson T.V., Master V.A. Review of the relationship between C-reactive protein and exercise. Mol. Diagn. Ther. 2011, 15(5):265-275.
108. Minghetti L., Ajmone-Cat M.A., De Berardinis M.A., De Simone R. Microglial activation in chronic neurodegenerative diseases: roles of apoptotic neurons and chronic stimulation. Brain Res. Brain Res. Rev. 2005, 48(2):251-256.
109. Monteiro-Junior R.S., Cevada T., Oliveira B.R., Lattari E., Portugal E.M., Carvalho A., Deslandes A.C. We need to move more: neurobiological hypotheses of physical exercise as a treatment for Parkinson's disease. Med. Hypotheses 2015, 85(5):537-541.
110. Moore S.A., Hallsworth K., Jakovljevic D.G., Blamire A.M., He J., Ford G.A., Rochester L., Trenell M.I. Effects of community exercise therapy on metabolic, brain, physical, and cognitive function following stroke: a randomized controlled pilot trial. Neurorehabil. Neural Repair 2014, 29(7):623-635.
111. Mori T., Koyama N., Arendash G.W., Horikoshi-Sakuraba Y., Tan J., Town T. Overexpression of human S100B exacerbates cerebral amyloidosis and gliosis in the Tg2576 mouse model of Alzheimer's disease. Glia 2010, 58(3):300-314.
112. Morris J.K., Bomhoff G.L., Gorres B.K., Davis V.A., Kim J., Lee P.P., Brooks W.M., Gerhardt G.A., Geiger P.C., Stanford J.A. Insulin resistance impairs nigrostriatal dopamine function. Exp. Neurol. 2011, 231(1):171-180.
113. Nagatsu T., Mogi M., Ichinose H., Togari A. Cytokines in Parkinson's disease. J. Neural Trans. Suppl. 2000, 58:143-151.
114. Neefkes-Zonneveld C.R., Bakkum A.J., Bishop N.C., van Tulder M.W., Janssen T.W. Effect of long-term physical activity and acute exercise on markers of systemic inflammation in persons with chronic spinal cord injury: a systematic review. Arch. Phys. Med. Rehabil. 2015, 96(1):30-42.
115. Neubauer O., Sabapathy S., Lazarus R., Jowett J.B., Desbrow B., Peake J.M., Cameron-Smith D., Haseler L.J., Wagner K.H., Bulmer A.C. Transcriptome analysis of neutrophils after endurance exercise reveals novel signaling mechanisms in the immune response to physiological stress. J. Appl. Physiol. (1985) 2013, 114(12):1677-1688.
116. Nichol K.E., Poon W.W., Parachikova A.I., Cribbs D.H., Glabe C.G., Cotman C.W. Exercise alters the immune profile in Tg2576 Alzheimer mice toward a response coincident with improved cognitive performance and decreased amyloid. J. Neuroinflammation 2008, 5:13.
117. Nieman D.C., Johanssen L.M., Lee J.W., Arabatzis K. Infectious episodes in runners before and after the Los Angeles Marathon. J. Sports Med. Phys. Fitness 1990, 30(3):316-328.
118. Noto C., Maes M., Ota V.K., Teixeira A.L., Bressan R.A., Gadelha A., Brietzke E. High predictive value of immune-inflammatory biomarkers for schizophrenia diagnosis and association with treatment resistance. World J. Biol. Psychiatry 2015, 10.3109/15622975.2015.1062552.
119. Nowotny K., Jung T., Hohn A., Weber D., Grune T. Advanced glycation end products and oxidative stress in type 2 diabetes mellitus. Biomolecules 2015, 5(1):194-222.
120. Nutt D.J. The neuropharmacology of serotonin and noradrenaline in depression. Int. Clin. Psychopharmacol. 2002, 17(Suppl. 1):S1-12.
121. Olah G., Heredi J., Menyhart A., Czinege Z., Nagy D., Fuzik J., Kocsis K., Knapp L., Krucso E., Gellert L., et al. Unexpected effects of peripherally administered kynurenic acid on cortical spreading depression and related blood-brain barrier permeability. Drug Des. Devel. Ther. 2013, 7:981-987.
122. Osborn G.G., Saunders A.V. Current treatments for patients with Alzheimer disease. J. Am. Osteopath. Assoc. 2010, 110(Suppl. 8):S16-26.
123. Ouchi Y., Yagi S., Yokokura M., Sakamoto M. Neuroinflammation in the living brain of Parkinson's disease. Parkinsonism Relat. Disord. 2009, 15(Suppl. 15):S200-204.
124. Packer N., Hoffman-Goetz L. Acute exercise increases hippocampal TNF-alpha, caspase-3 and caspase-7 expression in healthy young and older mice. J. Sports Med. Phys. Fitness 2015, 55(4):368-376.
125. Parajuli B., Sonobe Y., Kawanokuchi J., Doi Y., Noda M., Takeuchi H., Mizuno T., Suzumura A. GM-CSF increases LPS-induced production of proinflammatory mediators via upregulation of TLR4 and CD14 in murine microglia. J. Neuroinflammation 2012, 9:268.
126. Pedersen B.K. The anti-inflammatory effect of exercise: its role in diabetes and cardiovascular disease control. Essays Biochem. 2006, 42:105-117.
127. Peixoto T.C., Begot I., Bolzan D.W., Machado L., Reis M.S., Papa V., Carvalho A.C., Arena R., Gomes W.J., Guizilini S. Early exercise-based rehabilitation improves health-related quality of life and functional capacity after acute myocardial infarction: a randomized controlled trial. Can. J. Cardiol. 2015, 31(3):308-313.
128. Penkowa M., Giralt M., Lago N., Camats J., Carrasco J., Hernandez J., Molinero A., Campbell I.L., Hidalgo J. Astrocyte-targeted expression of IL-6 protects the CNS against a focal brain injury. Exp. Neurol. 2003, 181(2):130-148.
129. Piao C.S., Stoica B.A., Wu J., Sabirzhanov B., Zhao Z., Cabatbat R., Loane D.J., Faden A.I. Late exercise reduces neuroinflammation and cognitive dysfunction after traumatic brain injury. Neurobiol. Dis. 2013, 54:252-263.
130. Pies R.W. Depression and the pitfalls of causality: implications for DSM-V. J. Affect. Disord. 2009, 116(1-2):1-3.
131. Ploeger H.E., Takken T., de Greef M.H., Timmons B.W. The effects of acute and chronic exercise on inflammatory markers in children and adults with a chronic inflammatory disease: a systematic review. Exerc. Immunol. Rev. 2009, 15:6-41.
132. Powers M.B., Asmundson G.J., Smits J.A. Exercise for mood and anxiety disorders: the state-of-the science. Cogn. Behav. Ther. 2015, 44(4):237-239.
133. Prestes J., de Ferreira C.K., Dias R., Frollini A.B., Donatto F.F., Cury-Boaventura M.F., Guereschi M.G., Pithon-Curi T.C., Verlengia R., Palanch A.C., et al. Lymphocyte and cytokines after short periods of exercise. Int. J. Sports Med. 2008, 29(12):1010-1014.
134. Puhl S.L., Muller A., Wagner M., Devaux Y., Bohm M., Wagner D.R., Maack C. Exercise attenuates inflammation and limits scar thinning after myocardial infarction in mice. Am. J. Physiol. Heart Circ. Physiol. 2015, 309(2):H345-359.
135. Qian L., Flood P.M., Hong J.S. Neuroinflammation is a key player in Parkinson's disease and a prime target for therapy. J. Neural Trans. 2010, 117(8):971-979.
136. Qin L., Liu Y., Hong J.S., Crews F.T. NADPH oxidase and aging drive microglial activation, oxidative stress, and dopaminergic neurodegeneration following systemic LPS administration. Glia 2013, 61(6):855-868.
137. Radak Z., Kumagai S., Taylor A.W., Naito H., Goto S. Effects of exercise on brain function: role of free radicals. Appl. Physiol. Nutr. Metab. 2007, 32(5):942-946.
138. Radak Z., Silye G., Bartha C., Jakus J., Stefanovits-Banyai E., Atalay M., Marton O., Koltai E. The effects of cocoa supplementation, caloric restriction, and regular exercise: on oxidative stress markers of brain and memory in the rat model. Food Chem. Toxicol. 2013, 61:36-41.
139. Raedler T.J. Inflammatory mechanisms in major depressive disorder. Curr. Opin. Psychiatry 2011, 24(6):519-525.
140. Rajkowska G., Miguel-Hidalgo J.J., Wei J., Dilley G., Pittman S.D., Meltzer H.Y., Overholser J.C., Roth B.L., Stockmeier C.A. Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol. Psychiatry 1999, 45(9):1085-1098.
141. Rajkowska G., Hughes J., Stockmeier C.A., Javier Miguel-Hidalgo J., Maciag D. Coverage of blood vessels by astrocytic endfeet is reduced in major depressive disorder. Biol. Psychiatry 2013, 73(7):613-621.
142. Rao J.S., Rapoport S.I., Kim H.W. Altered neuroinflammatory, arachidonic acid cascade and synaptic markers in postmortem Alzheimer's disease brain. Transl. Psychiatry 2011, 1:e31.
143. Rao J.S., Kim H.W., Harry G.J., Rapoport S.I., Reese E.A. Increased neuroinflammatory and arachidonic acid cascade markers, and reduced synaptic proteins, in the postmortem frontal cortex from schizophrenia patients. Schizophr. Res. 2013, 147(1):24-31.
144. Rees K., Stowe R., Patel S., Ives N., Breen K., Clarke C.E., Ben-Shlomo Y. Non-steroidal anti-inflammatory drugs as disease-modifying agents for Parkinson's disease: evidence from observational studies. Cochrane Database Syst. Rev. 2011, 9(11):CD008454.
145. Rethorst C.D., Toups M.S., Greer T.L., Nakonezny P.A., Carmody T.J., Grannemann B.D., Huebinger R.M., Barber R.C., Trivedi M.H. Pro-inflammatory cytokines as predictors of antidepressant effects of exercise in major depressive disorder. Mol. Psychiatry 2013, 18(10):1119-1124.
146. Reynolds A.D., Glanzer J.G., Kadiu I., Ricardo-Dukelow M., Chaudhuri A., Ciborowski P., Cerny R., Gelman B., Thomas M.P., Mosley R.L., et al. Nitrated alpha-synuclein-activated microglial profiling for Parkinson's disease. J. Neurochem. 2008, 104(6):1504-1525.
147. Robinson E., Durrer C., Simtchouk S., Jung M.E., Bourne J.E., Voth E., Little J.P. Short-term high-intensity interval and moderate-intensity continuous training reduce leukocyte TLR4 in inactive adults at elevated risk of type 2 diabetes. J. Appl. Physiol. (1985) 2015, 119(5):508-516.
148. Rohde T., MacLean D.A., Richter E.A., Kiens B., Pedersen B.K. Prolonged submaximal eccentric exercise is associated with increased levels of plasma IL-6. Am. J. Physiol. 1997, 273(Pt 1):E85-91.
149. Roig M., Nordbrandt S., Geertsen S.S., Nielsen J.B. The effects of cardiovascular exercise on human memory: A review with meta-analysis. Neurosci. Biobehav. Rev. 2013, 37(8):1645-1666.
150. Rosety-Rodriguez M., Camacho A., Rosety I., Fornieles G., Rosety M.A., Diaz A.J., Bernardi M., Rosety M., Ordonez F.J. Low-grade systemic inflammation and leptin levels were improved by arm cranking exercise in adults with chronic spinal cord injury. Arch. Phys. Med. Rehabil. 2014, 95(2):297-302.
151. Rozovsky I., Finch C.E., Morgan T.E. Age-related activation of microglia and astrocytes: in vitro studies show persistent phenotypes of aging, increased proliferation, and resistance to down-regulation. Neurobiol. Aging 1998, 19(1):97-103.
152. Ruberg M., France-Lanord V., Brugg B., Lambeng N., Michel P.P., Anglade P., Hunot S., Damier P., Faucheux B., Hirsch E., et al. Neuronal death caused by apoptosis in Parkinson disease. Rev. Neurol. (Paris) 1997, 153(8-9):499-508.
153. Sanacora G., Treccani G., Popoli M. Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology 2012, 62(1):63-77.
154. Santiago J.A., Potashkin J.A. Shared dysregulated pathways lead to Parkinson's disease and diabetes. Trends Mol. Med. 2013, 19(3):176-186.
155. Scarmeas N., Luchsinger J.A., Schupf N., Brickman A.M., Cosentino S., Tang M.X., Stern Y. Physical activity, diet, and risk of Alzheimer disease. J. Am. Med. Assoc. 2009, 302(6):627-637.
156. Selkirk G.A., McLellan T.M., Wright H.E., Rhind S.G. Expression of intracellular cytokines, HSP72, and apoptosis in monocyte subsets during exertional heat stress in trained and untrained individuals. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2009, 296(3):R575-586.
157. Serrano-Pozo A., Mielke M.L., Gomez-Isla T., Betensky R.A., Growdon J.H., Frosch M.P., Hyman B.T. Reactive glia not only associates with plaques but also parallels tangles in Alzheimer's disease. Am. J. Pathol. 2011, 179(3):1373-1384.
158. Shockett P.E., Khanal J., Sitaula A., Oglesby C., Meachum W.A., Castracane V.D., Kraemer R.R. Plasma cell-free mitochondrial DNA declines in response to prolonged moderate aerobic exercise. Physiol. Rep. 2016, 4(1).
159. Smith J.A., Gray A.B., Pyne D.B., Baker M.S., Telford R.D., Weidemann M.J. Moderate exercise triggers both priming and activation of neutrophil subpopulations. Am. J. Physiol. 1996, 270(Pt 2):R838-845.
160. Sokolova A., Hill M.D., Rahimi F., Warden L.A., Halliday G.M., Shepherd C.E. Monocyte chemoattractant protein-1 plays a dominant role in the chronic inflammation observed in Alzheimer's disease. Brain Pathol. 2009, 19(3):392-398.
161. Spielman L.J., Little J.P., Klegeris A. Inflammation and insulin/IGF-1 resistance as the possible link between obesity and neurodegeneration. J. Neuroimmunol. 2014, 273:8-21.
162. Stahl S.M. Regulation of neurotransmitter receptors by desipramine and other antidepressant drugs: the neurotransmitter receptor hypothesis of antidepressant action. J. Clin. Psychiatry 1984, 45(Pt 2):37-45.
163. Starkie R., Ostrowski S.R., Jauffred S., Febbraio M., Pedersen B.K. Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans. FASEB J. 2003, 17(8):884-886.
164. Steensberg A., Fischer C.P., Keller C., Moller K., Pedersen B.K. IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans. Am. J. Physiol. Endocrinol. Metab. 2003, 285(2):E433-437.
165. Stewart L.K., Flynn M.G., Campbell W.W., Craig B.A., Robinson J.P., McFarlin B.K., Timmerman K.L., Coen P.M., Felker J., Talbert E. Influence of exercise training and age on CD14+ cell-surface expression of toll-like receptor 2 and 4. Brain Behav. Immun. 2005, 19(5):389-397.
166. Stojanovic M.D., Ostojic S.M., Calleja-Gonzalez J., Milosevic Z., Mikic M. Correlation between explosive strength, aerobic power and repeated sprint ability in elite basketball players. J. Sports Med. Phys. Fitness 2012, 52(4):375-381.
167. Stranska Z., Svacina S. Myokines-muscle tissue hormones. Vnitr. Lek. 2015, 61(4):365-368.
168. Stubbs B., Gardner-Sood P., Smith S., Ismail K., Greenwood K., Farmer R., Gaughran F. Sedentary behaviour is associated with elevated C-reactive protein levels in people with psychosis. Schizophr. Res. 2015, 168(1-2):461-464.
169. Suijo K., Inoue S., Ohya Y., Odagiri Y., Takamiya T., Ishibashi H., Itoh M., Fujieda Y., Shimomitsu T. Resistance exercise enhances cognitive function in mouse. Int. J. Sports Med. 2013, 34(4):368-375.
170. Swartz K.R., Liu F., Sewell D., Schochet T., Campbell I., Sandor M., Fabry Z. Interleukin-6 promotes post-traumatic healing in the central nervous system. Brain Res. 2001, 896(1-2):86-95.
171. Tapia-Rojas C., Aranguiz F., Varela-Nallar L., Inestrosa N.C. Voluntary running attenuates memory loss, decreases neuropathological changes and induces neurogenesis in a mouse model of Alzheimer's disease. Brain Pathol. 2016, 26(1):62-73.
172. Teismann P., Tieu K., Choi D.K., Wu D.C., Naini A., Hunot S., Vila M., Jackson-Lewis V., Przedborski S. Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration. Proc. Natl. Acad. Sci. U. S. A. 2003, 100(9):5473-5478.
173. Timmerman K.L., Flynn M.G., Coen P.M., Markofski M.M., Pence B.D. Exercise training-induced lowering of inflammatory (CD14+ CD16+) monocytes: a role in the anti-inflammatory influence of exercise?. J. Leukoc. Biol. 2008, 84(5):1271-1278.
174. Tissot R. The common pathophysiology of monaminergic psychoses: a new hypothesis. Neuropsychobiology 1975, 1(4):243-260.
175. Torres-Platas S.G., Cruceanu C., Chen G.G., Turecki G., Mechawar N. Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides. Brain Behav. Immun. 2014, 42:50-59.
176. Tucsek Z., Toth P., Sosnowska D., Gautam T., Mitschelen M., Koller A., Szalai G., Sonntag W.E., Ungvari Z., Csiszar A. Obesity in aging exacerbates blood-brain barrier disruption, neuroinflammation, and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and Alzheimer's disease. J. Gerontol. A. Biol. Sci. Med. Sci. 2014, 69(10):1212-1226.
177. Uc E.Y., Doerschug K.C., Magnotta V., Dawson J.D., Thomsen T.R., Kline J.N., Rizzo M., Newman S.R., Mehta S., Grabowski T.J., et al. Phase I/II randomized trial of aerobic exercise in Parkinson disease in a community setting. Neurology 2014, 83(5):413-425.
178. Uher R., Payne J.L., Pavlova B., Perlis R.H. Major depressive disorder in DSM-5: implications for clinical practice and research of changes from DSM-IV. Depress. Anxiety 2014, 31(6):459-471.
179. Uysal N., Kiray M., Sisman A.R., Camsari U.M., Gencoglu C., Baykara B., Cetinkaya C., Aksu I. Effects of voluntary and involuntary exercise on cognitive functions, and VEGF and BDNF levels in adolescent rats. Biotech. Histochem. 2015, 90(1):55-68.
180. Valkanova V., Ebmeier K.P., Allan C.L. CRP, IL-6 and depression: a systematic review and meta-analysis of longitudinal studies. J. Affect. Disord. 2013, 150(3):736-744.
181. Varnum M.M., Ikezu T. The classification of microglial activation phenotypes on neurodegeneration and regeneration in Alzheimer's disease brain. Arch. Immunol. Ther. Exp. (Warsz) 2012, 60(4):251-266.
182. Weinberg L., Hasni A., Shinohara M., Duarte A. A single bout of resistance exercise can enhance episodic memory performance. Acta Psychol. (Amst) 2014, 153:13-19.
183. Weisberg S.P., McCann D., Desai M., Rosenbaum M., Leibel R.L., Ferrante A.W. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 2003, 112(12):1796-1808.
184. Wise R.A., Bozarth M.A. Brain mechanisms of drug reward and euphoria. Psychiatry Med. 1985, 3(4):445-460.
185. Xu L. Neural plasticity mechanism of depression. Zhong. Nan. Da. Xue. Xue. Bao. Yi. Xue. Ban. 2008, 33(4):326-330.
186. Yu Q., Li X., Wang J., Li Y. Effect of exercise training on long-term potentiation and NMDA receptor channels in rats with cerebral infarction. Exp. Ther. Med. 2013, 6(6):1431-1436.
187. Yu J.L., Ma L., Ma L., Tao Y.Z. Voluntary wheel running enhances cell proliferation and expression levels of BDNF, IGF1 and WNT4 in dentate gyrus of adult mice. Sheng. Li. Xue. Bao. 2014, 66(5):559-568.
188. Zhang W., Wang T., Pei Z., Miller D.S., Wu X., Block M.L., Wilson B., Zhang W., Zhou Y., Hong J.S., et al. Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson's disease. FASEB J. 2005, 19(6):533-542.
189. Zhao G., Liu H.L., Zhang H., Tong X.J. Treadmill exercise enhances synaptic plasticity, but does not alter beta-amyloid deposition in hippocampi of aged APP/PS1 transgenic mice. Neuroscience 2015, 298:357-366.
190. Zinger A., Barcia C., Herrero M.T., Guillemin G.J. The involvement of neuroinflammation and kynurenine pathway in Parkinson's disease. Parkinsons Dis. 2011, 2011:716859.
191. Zoladz J.A., Majerczak J., Zeligowska E., Mencel J., Jaskolski A., Jaskolska A., Marusiak J. Moderate-intensity interval training increases serum brain-derived neurotrophic factor level and decreases inflammation in Parkinson's disease patients. J. Physiol. Pharmacol. 2014, 65(3):441-448.
192. Zoppini G., Targher G., Zamboni C., Venturi C., Cacciatori V., Moghetti P., Muggeo M. Effects of moderate-intensity exercise training on plasma biomarkers of inflammation and endothelial dysfunction in older patients with type 2 diabetes. Nutr. Metab. Cardiovasc. Dis. 2006, 16(8):543-549.
193. Zou Y.M., Tan J.P., Li N., Yang J.S., Yu B.C., Yu J.M., Zhao Y.M., Wang L.N. Do physical exercise and reading reduce the risk of Parkinson's disease?: a cross-sectional study on factors associated with Parkinson's disease in elderly Chinese veterans. Neuropsychiatr. Dis. Treat. 2015, 11:695-700.
194. de Andrade L.P., Gobbi L.T., Coelho F.G., Christofoletti G., Costa J.L., Stella F. Benefits of multimodal exercise intervention for postural control and frontal cognitive functions in individuals with Alzheimer's disease: a controlled trial. J. Am. Geriatr. Soc. 2013, 61(11):1919-1926.
195. van der Sluijs K.F., van Elden L.J., Nijhuis M., Schuurman R., Pater J.M., Florquin S., Goldman M., Jansen H.M., Lutter R., van der Poll T. IL-10 is an important mediator of the enhanced susceptibility to pneumococcal pneumonia after influenza infection. J. Immunol. 2004, 172(12):7603-7609.