Volume 78, Issue 2
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645


Cerebrospinal fluid (CSF) and serum levels of 12 cytokines or chemokines important in central nervous system (CNS) infections were measured in 76 Ugandan children with cerebral malaria (CM) and 8 control children. As compared with control children, children with cerebral malaria had higher cerebrospinal fluid levels of interleukin (IL)-6, CXCL-8/IL-8, granulocyte-colony stimulating factor (G-CSF), tumor necrosis factor-α (TNF-α), and IL-1 receptor antagonist. There was no correlation between cerebrospinal and serum cytokine levels for any cytokine except G-CSF. Elevated cerebrospinal fluid but not serum TNF-α levels on admission were associated with an increased risk of neurologic deficits 3 months later (odds ratio 1.55, 95% CI: 1.10, 2.18, = 0.01) and correlated negatively with age-adjusted scores for attention (Spearman rho, −0.34, = 0.04) and working memory (Spearman rho, −0.32, = 0.06) 6 months later. In children with cerebral malaria, central nervous system TNF-α production is associated with subsequent neurologic and cognitive morbidity.


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  1. Murphy SC, Breman JG, 2001. Gaps in the childhood malaria burden in Africa: cerebral malaria, neurological sequelae, anemia, respiratory distress, hypoglycemia, and complications of pregnancy. Am J Trop Med Hyg 64 : 57–67.
  2. Hunt NH, Golenser J, Chan-Ling T, Parekh S, Rae C, Potter S, Medana IM, Miu J, Ball HJ, 2006. Immunopathogenesis of cerebral malaria. Int J Parasitol 36 : 569–582.
  3. Maheshwari RK, 1990. The role of cytokines in malaria infection. Bull World Health Organ 68 (Suppl): 138–144.
  4. Schofield L, Ferreira A, Altszuler R, Nussenzweig V, Nussenzweig RS, 1987. Interferon-gamma inhibits the intrahepatocytic development of malaria parasites in vitro. J Immunol 139 : 2020–2025.
  5. Grau GE, Heremans H, Piguet PF, Pointaire P, Lambert PH, Billiau A, Vassalli P, 1989. Monoclonal antibody against interferon gamma can prevent experimental cerebral malaria and its associated overproduction of tumor necrosis factor. Proc Natl Acad Sci U S A 86 : 5572–5574.
  6. Lou J, Donati YR, Juillard P, Giroud C, Vesin C, Mili N, Grau GE, 1997. Platelets play an important role in TNF-induced microvascular endothelial cell pathology. Am J Pathol 151 : 1397–1405.
  7. Wassmer SC, Combes V, Candal FJ, Juhan-Vague I, Grau GE, 2006. Platelets potentiate brain endothelial alterations induced by Plasmodium falciparum. Infect Immun 74 : 645–653.
  8. Medana IM, Hunt NH, Chan-Ling T, 1997. Early activation of microglia in the pathogenesis of fatal murine cerebral malaria. Glia 19 : 91–103.
  9. Schluesener HJ, Kremsner PG, Meyermann R, 1998. Widespread expression of MRP8 and MRP14 in human cerebral malaria by microglial cells. Acta Neuropathol (Berl) 96 : 575–580.
  10. Ma N, Madigan MC, Chan-Ling T, Hunt NH, 1997. Compromised blood-nerve barrier, astrogliosis, and myelin disruption in optic nerves during fatal murine cerebral malaria. Glia 19 : 135–151.
  11. Medana IM, Hunt NH, Chaudhri G, 1997. Tumor necrosis factor-alpha expression in the brain during fatal murine cerebral malaria: evidence for production by microglia and astrocytes. Am J Pathol 150 : 1473–1486.
  12. de Kossodo S, Grau GE, 1993. Profiles of cytokine production in relation with susceptibility to cerebral malaria. J Immunol 151 : 4811–4820.
  13. Armah H, Dodoo AK, Wiredu EK, Stiles JK, Adjei AA, Gyasi RK, Tettey Y, 2005. High-level cerebellar expression of cytokines and adhesion molecules in fatal, paediatric, cerebral malaria. Ann Trop Med Parasitol 99 : 629–647.
  14. Sarfo BY, Singh S, Lillard JW, Quarshie A, Gyasi RK, Armah H, Adjei AA, Jolly P, Stiles JK, 2004. The cerebral-malaria-associated expression of RANTES, CCR3 and CCR5 in postmortem tissue samples. Ann Trop Med Parasitol 98 : 297–303.
  15. Boivin MJ, Bangirana P, Byarugaba J, Opoka RO, Idro R, Jurek AM, John CC, 2007. Cognitive impairment after cerebral malaria in children: a prospective study. Pediatrics 119 : e360–e366.
  16. John CC, Opika-Opoka R, Byarugaba J, Idro R, Boivin MJ, 2006. Low levels of RANTES are associated with mortality in children with cerebral malaria. J Infect Dis 194 : 837–845.
  17. Lyke KE, Burges R, Cissoko Y, Sangare L, Dao M, Diarra I, Kone A, Harley R, Plowe CV, Doumbo OK, Sztein MB, 2004. Serum levels of the proinflammatory cytokines interleukin-1 beta (IL-1beta), IL-6, IL-8, IL-10, tumor necrosis factor alpha, and IL-12(p70) in Malian children with severe Plasmodium falciparum malaria and matched uncomplicated malaria or healthy controls. Infect Immun 72 : 5630–5637.
  18. Brown H, Rogerson S, Taylor T, Tembo M, Mwenechanya J, Molyneux M, Turner G, 2001. Blood-brain barrier function in cerebral malaria in Malawian children. Am J Trop Med Hyg 64 : 207–213.
  19. Medana IM, Chaudhri G, Chan-Ling T, Hunt NH, 2001. Central nervous system in cerebral malaria: ‘ innocent bystander ’ or active participant in the induction of immunopathology? Immunol Cell Biol 79 : 101–120.
  20. Ohga S, Okada K, Ueda K, Takada H, Ohta M, Aoki T, Kinukawa N, Miyazaki S, Hara T, 1999. Cerebrospinal fluid cytokine levels and dexamethasone therapy in bacterial meningitis. J Infect 39 : 55–60.
  21. Winter PM, Dung NM, Loan HT, Kneen R, Wills B, Thu le T, House D, White NJ, Farrar JJ, Hart CA, Solomon T, 2004. Proinflammatory cytokines and chemokines in humans with Japanese encephalitis. J Infect Dis 190 : 1618–1626.
  22. Grygorczuk S, Pancewicz S, Zajkowska J, Kondrusik M, Rwierz-binska R, Hermanowska-Szpakowicz T, 2004. Concentrations of macrophage inflammatory proteins MIP-1alpha and MIP-1beta and interleukin 8 (il-8) in lyme borreliosis. Infection 32 : 350–355.
  23. Inaba Y, Ishiguro A, Shimbo T, 1997. The production of macrophage inflammatory protein-1alpha in the cerebrospinal fluid at the initial stage of meningitis in children. Pediatr Res 42 : 788–793.
  24. Lin TY, Hsia SH, Huang YC, Wu CT, Chang LY, 2003. Proin-flammatory cytokine reactions in enterovirus 71 infections of the central nervous system. Clin Infect Dis 36 : 269–274.
  25. Matsubara T, Matsuoka T, Katayama K, Yoshitomi T, Nishikawa M, Ichiyama T, Furukawa S, 2000. Mononuclear cells and cytokines in the cerebrospinal fluid of echovirus 30 meningitis patients. Scand J Infect Dis 32 : 471–474.
  26. Ohga S, Aoki T, Okada K, Akeda H, Fujioka K, Ohshima A, Mori T, Minamishima I, Ueda K, 1994. Cerebrospinal fluid concentrations of interleukin-1 beta, tumour necrosis factor-alpha, and interferon gamma in bacterial meningitis. Arch Dis Child 70 : 123–125.
  27. Rosler A, Pohl M, Braune HJ, Oertel WH, Gemsa D, Sprenger H, 1998. Time course of chemokines in the cerebrospinal fluid and serum during herpes simplex type 1 encephalitis. J Neurol Sci 157 : 82–89.
  28. Shimoda K, Okamura S, Omori F, Mizuno Y, Hara T, Aoki T, Ueda K, Niho Y, 1991. Granulocyte colony-stimulating factor in cerebrospinal fluid from patients with meningitis. Blood 77 : 2214–2217.
  29. Siddiqui AA, Brouwer AE, Wuthiekanun V, Jaffar S, Shattock R, Irving D, Sheldon J, Chierakul W, Peacock S, Day N, White NJ, Harrison TS, 2005. IFN-gamma at the site of infection determines rate of clearance of infection in cryptococcal meningitis. J Immunol 174 : 1746–1750.
  30. Silveira RC, Procianoy RS, 2003. Interleukin-6 and tumor necrosis factor-alpha levels in plasma and cerebrospinal fluid of term newborn infants with hypoxic-ischemic encephalopathy. J Pediatr 143 : 625–629.
  31. van Deuren M, van der Ven-Jongekrijg J, Vannier E, van Dalen R, Pesman G, Bartelink AK, Dinarello CA, van der Meer JW, 1997. The pattern of interleukin-1beta (IL-1beta) and its modulating agents IL-1 receptor antagonist and IL-1 soluble receptor type II in acute meningococcal infections. Blood 90 : 1101–1108.
  32. van Furth AM, Seijmonsbergen EM, Langermans JA, Groeneveld PH, de Bel CE, van Furth R, 1995. High levels of interleukin 10 and tumor necrosis factor alpha in cerebrospinal fluid during the onset of bacterial meningitis. Clin Infect Dis 21 : 220–222.
  33. Yilmaz E, Gurgoze MK, Ilhan N, Dogan Y, Aydinoglu H, 2002. Interleukin-8 levels in children with bacterial, tuberculous and aseptic meningitis. Indian J Pediatr 69 : 219–221.
  34. Yokoyama T, Oda M, Seino Y, 1998. Interleukin-1 beta and interleukin-1 receptor antagonist levels in cerebrospinal fluid of aseptic meningitis patients. Pediatr Allergy Immunol 9 : 91–96.
  35. Holm S, 1979. A simple sequentially rejective multiple test procedure. Scand J Statis 6 : 65–70.
  36. Jennings VM, Actor JK, Lal AA, Hunter RL, 1997. Cytokine profile suggesting that murine cerebral malaria is an encephalitis. Infect Immun 65 : 4883–4887.
  37. World Health Organization, 2000. Severe falciparum malaria. World Health Organization, Communicable Diseases Cluster. Trans R Soc Trop Med Hyg 94 (Suppl 1): S1–90.
  38. Brown H, Hien TT, Day N, Mai NT, Chuong LV, Chau TT, Loc PP, Phu NH, Bethell D, Farrar J, Gatter K, White N, Turner G, 1999. Evidence of blood–brain barrier dysfunction in human cerebral malaria. Neuropathol Appl Neurobiol 25 : 331–340.
  39. Esamai F, Ernerudh J, Janols H, Welin S, Ekerfelt C, Mining S, Forsberg P, 2003. Cerebral malaria in children: serum and cerebrospinal fluid TNF-alpha and TGF-beta levels and their relationship to clinical outcome. J Trop Pediatr 49 : 216–223.
  40. Grau GE, Taylor TE, Molyneux ME, Wirima JJ, Vassalli P, Hommel M, Lambert PH, 1989. Tumor necrosis factor and disease severity in children with falciparum malaria. N Engl J Med 320 : 1586–1591.
  41. Brown H, Turner G, Rogerson S, Tembo M, Mwenechanya J, Molyneux M, Taylor T, 1999. Cytokine expression in the brain in human cerebral malaria. J Infect Dis 180 : 1742–1746.
  42. Adams S, Brown H, Turner G, 2002. Breaking down the blood–brain barrier: signaling a path to cerebral malaria? Trends Parasitol 18 : 360–366.
  43. Rock RB, Gekker G, Hu S, Sheng WS, Cheeran M, Lokensgard JR, Peterson PK, 2004. Role of microglia in central nervous system infections. Clin Microbiol Rev 17 : 942–964.
  44. Lokensgard JR, Hu S, Sheng W, vanOijen M, Cox D, Cheeran MC, Peterson PK, 2001. Robust expression of TNF-alpha, IL-1beta, RANTES, and IP-10 by human microglial cells during nonproductive infection with herpes simplex virus. J Neurovirol 7 : 208–219.
  45. Frei K, Malipiero UV, Leist TP, Zinkernagel RM, Schwab ME, Fontana A, 1989. On the cellular source and function of interleukin 6 produced in the central nervous system in viral diseases. Eur J Immunol 19 : 689–694.
  46. Lipovsky MM, Gekker G, Hu S, Ehrlich LC, Hoepelman AI, Peterson PK, 1998. Cryptococcal glucuronoxylomannan induces interleukin (IL)-8 production by human microglia but inhibits neutrophil migration toward IL-8. J Infect Dis 177 : 260–263.
  47. Babcock AA, Kuziel WA, Rivest S, Owens T, 2003. Chemokine expression by glial cells directs leukocytes to sites of axonal injury in the CNS. J Neurosci 23 : 7922–7930.
  48. McManus CM, Brosnan CF, Berman JW, 1998. Cytokine induction of MIP-1 alpha and MIP-1 beta in human fetal microglia. J Immunol 160 : 1449–1455.
  49. Croitoru-Lamoury J, Guillemin GJ, Dormont D, Brew BJ, 2003. Quinolinic acid up-regulates chemokine production and chemokine receptor expression in astrocytes. Adv Exp Med Biol 527 : 37–45.
  50. Aloisi F, Care A, Borsellino G, Gallo P, Rosa S, Bassani A, Cabibbo A, Testa U, Levi G, Peschle C, 1992. Production of hemolymphopoietic cytokines (IL-6, IL-8, colony-stimulating factors) by normal human astrocytes in response to IL-1 beta and tumor necrosis factor-alpha. J Immunol 149 : 2358–2366.
  51. Ghoshal A, Das S, Ghosh S, Mishra MK, Sharma V, Koli P, Sen E, Basu A, 2007. Proinflammatory mediators released by activated microglia induces neuronal death in Japanese encephalitis. Glia 55 : 483–496.
  52. van Deuren M, van der Ven-Jongekrijg J, Demacker PN, Bartelink AK, van Dalen R, Sauerwein RW, Gallati H, Vannice JL, van der Meer JW, 1994. Differential expression of proinflammatory cytokines and their inhibitors during the course of meningococcal infections. J Infect Dis 169 : 157–161.
  53. Strack A, Asensio VC, Campbell IL, Schluter D, Deckert M, 2002. Chemokines are differentially expressed by astrocytes, microglia and inflammatory leukocytes in Toxoplasma encephalitis and critically regulated by interferon-gamma. Acta Neuropathol (Berl) 103 : 458–468.
  54. Lahrtz F, Piali L, Spanaus KS, Seebach J, Fontana A, 1998. Chemokines and chemotaxis of leukocytes in infectious meningitis. J Neuroimmunol 85 : 33–43.
  55. Lopez-Cortes LF, Cruz-Ruiz M, Gomez-Mateos J, Viciana-Fernandez P, Martinez-Marcos FJ, Pachon J, 1995. Interleukin-8 in cerebrospinal fluid from patients with meningitis of different etiologies: its possible role as neutrophil chemotactic factor. J Infect Dis 172 : 581–584.
  56. Ertel W, Keel M, Buergi U, Hartung T, Imhof HG, Trentz O, 1999. Granulocyte colony-stimulating factor inhibits neutrophil apoptosis at the local site after severe head and thoracic injury. J Trauma 46 : 784–792.
  57. Chen L, Zhang Z, Sendo F, 2000. Neutrophils play a critical role in the pathogenesis of experimental cerebral malaria. Clin Exp Immunol 120 : 125–133.
  58. Kushi H, Saito T, Makino K, Hayashi N, 2003. IL-8 is a key mediator of neuroinflammation in severe traumatic brain injuries. Acta Neurochir Suppl (Wien) 86 : 347–350.
  59. Maier B, Schwerdtfeger K, Mautes A, Holanda M, Muller M, Steudel WI, Marzi I, 2001. Differential release of interleukines 6, 8, and 10 in cerebrospinal fluid and plasma after traumatic brain injury. Shock 15 : 421–426.
  60. Galimberti D, Schoonenboom N, Scheltens P, Fenoglio C, Bouwman F, Venturelli E, Guidi I, Blankenstein MA, Bresolin N, Scarpini E, 2006. Intrathecal chemokine synthesis in mild cognitive impairment and Alzheimer disease. Arch Neurol 63 : 538–543.
  61. Clark IA, Ilschner S, MacMicking JD, Cowden WB, 1990. TNF and Plasmodium berghei ANKA-induced cerebral malaria. Immunol Lett 25 : 195–198.
  62. Chao CC, Hu S, 1994. Tumor necrosis factor-alpha potentiates glutamate neurotoxicity in human fetal brain cell cultures. Dev Neurosci 16 : 172–179.
  63. Chao CC, Hu S, Ehrlich L, Peterson PK, 1995. Interleukin-1 and tumor necrosis factor-alpha synergistically mediate neurotoxicity: involvement of nitric oxide and of N-methyl-D-aspartate receptors. Brain Behav Immun 9 : 355–365.
  64. Chao CC, Hu S, Sheng WS, Tsang M, Peterson PK, 1995. Tumor necrosis factor-alpha mediates the release of bioactive transforming growth factor-beta in murine microglial cell cultures. Clin Immunol Immunopathol 77 : 358–365.
  65. van Hensbroek MB, Palmer A, Onyiorah E, Schneider G, Jaffar S, Dolan G, Memming H, Frenkel J, Enwere G, Bennett S, Kwiatkowski D, Greenwood B, 1996. The effect of a monoclonal antibody to tumor necrosis factor on survival from childhood cerebral malaria. J Infect Dis 174 : 1091–1097.
  66. Sprenger H, Rosler A, Tonn P, Braune HJ, Huffmann G, Gemsa D, 1996. Chemokines in the cerebrospinal fluid of patients with meningitis. Clin Immunol Immunopathol 80 : 155–161.

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  • Received : 06 Oct 2007
  • Accepted : 16 Nov 2007

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