Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

The role of cytokines in mediating effects of prenatal infection on the fetus: implications for schizophrenia

Molecular Psychiatry volume 11, pages 47–55 (2006)Cite this article

Abstract

Maternal infections with bacterial or viral agents during pregnancy are associated with an increased incidence of schizophrenia in the offspring at adulthood although little is known about the mechanism by which maternal infection might affect fetal neurodevelopment. Exposure of pregnant rodents to the bacterial endotoxin, lipopolysaccharide (LPS), results in behavioral deficits in the adult offspring that are relevant to schizophrenia. It is however unknown whether these effects are due to the direct action of the inflammatory stimulus on the developing fetus, or due to secondary immune mediators (cytokines) activated at maternal/fetal sites. In this study we sought to elucidate the site of action of LPS, following a single intraperitoneal (i.p.) injection, in pregnant rats at gestation day 18. Animals received 5 μCi of iodinated LPS (125I-LPS) and its distribution was assessed in maternal/fetal tissues (1–8 h). In addition, induction of the inflammatory cytokines, TNF-α, IL-1β and IL-6, was measured in maternal/fetal tissues following maternal LPS challenge (0.05 mg/kg, i.p.) (2–8 h). 125I-LPS was detected in maternal tissues and placenta, but not the fetus. This distribution was accompanied by significant increases in TNF-α, IL-1β and IL-6 in maternal plasma and placenta, but not in fetal liver or brain. A significant increase in IL-1β was however detected in fetal plasma, possibly due to transfer from the maternal circulation or placenta. Collectively, these data suggest that effects of maternal LPS exposure on the developing fetal brain are not mediated by the direct action of LPS, but via indirect actions at the level of the maternal circulation or placenta.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Gourion D, Gourevitch R, Leprovost JB, Olie HLJ, Krebs MO . Neurodevelopmental hypothesis in schizophrenia. Encephale 2004; 30: 109–118.

    Article  CAS  Google Scholar 

  2. Tsuang M . Schizophrenia: genes and environment. Biol Psychiatry 2000; 47: 210–220.

    Article  CAS  Google Scholar 

  3. Boog G . Obstetrical complications and subsequent schizophrenia in adolescent and young adult offsprings: is there a relationship? Eur J Obstet Gynecol Reprod Biol 2004; 114: 130–136.

    Article  Google Scholar 

  4. Marcelis M, Navarro-Mateu F, Murray R, Selten JP, Van Os J . Urbanization and psychosis: a study of 1942–1978 birth cohorts in The Netherlands. Psychol Med 1998; 28: 871–879.

    Article  CAS  Google Scholar 

  5. O'Callaghan E, Sham PC, Takei N, Murray G, Glover G, Hare EH et al. The relationship of schizophrenic births to 16 infectious diseases. Br J Psychiatry 1994; 165: 353–356.

    Article  CAS  Google Scholar 

  6. Mednick SA, Machon RA, Huttunen MO, Bonett D . Adult schizophrenia following prenatal exposure to an influenza epidemic. Arch Gen Psychiatry 1988; 45: 189–192.

    Article  CAS  Google Scholar 

  7. Torrey EF, Rawlings R, Waldman IN . Schizophrenic births and viral diseases in two states. Schizophr Res 1988; 1: 73–77.

    Article  CAS  Google Scholar 

  8. Suvisaari J, Haukka J, Tanskanen A, Hovi T, Lonnqvist J . Association between prenatal exposure to poliovirus infection and adult schizophrenia. Am J Psychiatry 1999; 156: 1100–1102.

    PubMed  CAS  Google Scholar 

  9. Buka SL, Tsuang MT, Torrey EF, Klebanoff MA, Bernstein D, Yolken RH . Maternal infections and subsequent psychosis among offspring. Arch Gen Psychiatry 2001; 58: 1032–1037.

    Article  CAS  Google Scholar 

  10. Watson CG, Kucala T, Tilleskjor C, Jacobs L . Schizophrenic birth seasonality in relation to the incidence of infectious diseases and temperature extremes. Arch Gen Psychiatry 1984; 41: 85–90.

    Article  CAS  Google Scholar 

  11. Shi L, Fatemi SH, Sidwell RW, Patterson PH . Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J Neurosci 2003; 23: 297–302.

    Article  Google Scholar 

  12. Zuckerman L, Rehavi M, Nachman R, Weiner I . Immune activation during pregnancy in rats leads to a postpubertal emergence of disrupted latent inhibition, dopaminergic hyperfunction, and altered limbic morphology in the offspring: a novel neurodevelopmental model of schizophrenia. Neuropsychopharmacology 2003; 28: 1778–1789.

    Article  CAS  Google Scholar 

  13. Zuckerman L, Weiner I . Post-pubertal emergence of disrupted latent inhibition following prenatal immune activation. Psychopharmacology (Berl) 2003; 169: 308–313.

    Article  CAS  Google Scholar 

  14. Zuckerman L, Weiner I . Maternal immune activation leads to behavioral and pharmacological changes in the adult offspring. J Psychiatr Res 2005; 39: 311–323.

    Article  Google Scholar 

  15. Borrell J, Vela JM, Arevalo-Martin A, Molina-Holgado E, Guaza C . Prenatal immune challenge disrupts sensorimotor gating in adult rats. Implications for the etiopathogenesis of schizophrenia. Neuropsychopharmacology 2002; 26: 204–215.

    Article  CAS  Google Scholar 

  16. Fortier ME, Joober R, Luheshi GN, Boksa P . Maternal exposure to bacterial endotoxin during pregnancy enhances amphetamine-induced locomotion and startle responses in adult rat offspring. J Psychiatr Res 2004; 38: 335–345.

    Article  Google Scholar 

  17. Borish LC, Steinke JW . 2. Cytokines and chemokines. J Allergy Clin Immunol 2003; 111 (2 Suppl): S460–S475.

    Article  CAS  Google Scholar 

  18. Dantzer R, Wollman EE . Relationships between the brain and the immune system. J Soc Biol 2003; 197: 81–88.

    Article  Google Scholar 

  19. Luheshi GN . Cytokines and fever. Mechanisms and sites of action. Ann N Y Acad Sci 1998; 856: 83–89.

    Article  CAS  Google Scholar 

  20. Dammann O, Leviton A . Infection remote from the brain, neonatal white matter damage, and cerebral palsy in the preterm infant. Semin Pediatr Neurol 1998; 5: 190–201.

    Article  CAS  Google Scholar 

  21. Zhao B, Schwartz JP . Involvement of cytokines in normal CNS development and neurological diseases: recent progress and perspectives. J Neurosci Res 1998; 52: 7–16.

    Article  CAS  Google Scholar 

  22. Allan SM, Rothwell NJ . Inflammation in central nervous system injury. Philos Trans R Soc Lond B Biol Sci 2003; 358: 1669–1677.

    Article  CAS  Google Scholar 

  23. Marx CE, Jarskog LF, Lauder JM, Lieberman JA, Gilmore JH . Cytokine effects on cortical neuron MAP-2 immunoreactivity: implications for schizophrenia. Biol Psychiatry 2001; 50: 743–749.

    Article  CAS  Google Scholar 

  24. Cai Z, Pan ZL, Pang Y, Evans OB, Rhodes PG . Cytokine induction in fetal rat brains and brain injury in neonatal rats after maternal lipopolysaccharide administration. Pediatr Res 2000; 47: 64–72.

    Article  CAS  Google Scholar 

  25. Urakubo A, Jarskog LF, Lieberman JA, Gilmore JH . Prenatal exposure to maternal infection alters cytokine expression in the placenta, amniotic fluid, and fetal brain. Schizophr Res 2001; 47: 27–36.

    Article  CAS  Google Scholar 

  26. Chow JC, Young DW, Golenbock DT, Christ WJ, Gusovsky F . Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction. J Biol Chem 1999; 274: 10689–10692.

    Article  CAS  Google Scholar 

  27. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998; 282: 2085–2088.

    Article  CAS  Google Scholar 

  28. Rivest S . Molecular insights on the cerebral innate immune system. Brain Behav Immun 2003; 17: 13–19.

    Article  CAS  Google Scholar 

  29. Eklind S, Mallard C, Leverin AL, Gilland E, Blomgren K, Mattsby-Baltzer I et al. Bacterial endotoxin sensitizes the immature brain to hypoxic–ischaemic injury. Eur J Neurosci 2001; 13: 1101–1106.

    Article  CAS  Google Scholar 

  30. Maslinska D, Laure-Kamionowska M, Maslinski S . Toll-like receptors in rat brains injured by hypoxic-ischaemia or exposed to staphylococcal alpha-toxin. Folia Neuropathol 2004; 42: 125–132.

    PubMed  CAS  Google Scholar 

  31. Laflamme N, Rivest S . Toll-like receptor 4: the missing link of the cerebral innate immune response triggered by circulating gram-negative bacterial cell wall components. FASEB J 2001; 15: 155–163.

    Article  CAS  Google Scholar 

  32. Hua LL, Lee SC . Distinct patterns of stimulus-inducible chemokine mRNA accumulation in human fetal astrocytes and microglia. Glia 2000; 30: 74–81.

    Article  CAS  Google Scholar 

  33. Kato M, Ohno K, Takeshita K, Herz F . Stimulation of human fetal astrocyte proliferation by bacterial lipopolysaccharides and lipid A. Acta Neuropathol (Berl) 1991; 82: 384–388.

    Article  CAS  Google Scholar 

  34. Romero LI, Schettini G, Lechan RM, Dinarello CA, Reichlin S . Bacterial lipopolysaccharide induction of IL-6 in rat telencephalic cells is mediated in part by IL-1. Neuroendocrinology 1993; 57: 892–897.

    Article  CAS  Google Scholar 

  35. Wei R, Phillips TM, Sternberg EM . Specific up-regulation of CRH or AVP secretion by acetylcholine or lipopolysaccharide in inflammatory susceptible Lewis rat fetal hypothalamic cells. J Neuroimmunol 2002; 131: 31–40.

    Article  CAS  Google Scholar 

  36. Yamasu K, Onoe H, Soma G, Oshima H, Mizuno D . Secretion of tumor necrosis factor during fetal and neonatal development of the mouse: ontogenic inflammation. J Biol Response Mod 1989; 8: 644–655.

    PubMed  CAS  Google Scholar 

  37. Goto M, Yoshioka T, Ravindranath T, Battelino T, Young RI, Zeller WP . LPS injected into the pregnant rat late in gestation does not induce fetal endotoxemia. Res Commun Mol Pathol Pharmacol 1994; 85: 109–112.

    PubMed  CAS  Google Scholar 

  38. Kohmura Y, Kirikae T, Kirikae F, Nakano M, Sato I . Lipopolysaccharide (LPS)-induced intra-uterine fetal death (IUFD) in mice is principally due to maternal cause but not fetal sensitivity to LPS. Microbiol Immunol 2000; 44: 897–904.

    Article  CAS  Google Scholar 

  39. Ulevitch RJ . The preparation and characterization of a radioiodinated bacterial lipopolysaccharide. Immunochemistry 1978; 15: 157–164.

    Article  CAS  Google Scholar 

  40. Rees GS, Ball C, Ward HL, Gee CK, Tarrant G, Mistry Y et al. Rat interleukin 6: expression in recombinant Escherichia coli, purification and development of a novel ELISA. Cytokine 1999; 11: 95–103.

    Article  CAS  Google Scholar 

  41. Romero R, Lafreniere D, Duff GW, Kadar N, Durum S, Hobbins JC . Failure of endotoxin to cross the chorioamniotic membranes in vitro. Am J Perinatol 1987; 4: 360–362.

    Article  CAS  Google Scholar 

  42. Enders AC, Carter AM . What can comparative studies of placental structure tell us? A review. Placenta 2004; 25 (Suppl A): S3–S9.

    Article  CAS  Google Scholar 

  43. Robinson NR, Atkinson DE, Jones CJ, Sibley CP . Permeability of the near-term rat placenta to hydrophilic solutes. Placenta 1988; 9: 361–372.

    Article  CAS  Google Scholar 

  44. Buka SL, Tsuang MT, Torrey EF, Klebanoff MA, Wagner RL, Yolken RH . Maternal cytokine levels during pregnancy and adult psychosis. Brain Behav Immun 2001; 15: 411–420.

    Article  CAS  Google Scholar 

  45. Bowen JM, Chamley L, Keelan JA, Mitchell MD . Cytokines of the placenta and extra-placental membranes: roles and regulation during human pregnancy and parturition. Placenta 2002; 23: 257–273.

    Article  CAS  Google Scholar 

  46. Silen ML, Firpo A, Morgello S, Lowry SF, Francus T . Interleukin-1 alpha and tumor necrosis factor alpha cause placental injury in the rat. Am J Pathol 1989; 135: 239–244.

    PubMed  PubMed Central  CAS  Google Scholar 

  47. Saito S . Cytokine cross-talk between mother and the embryo/placenta. J Reprod Immunol 2001; 52: 15–33.

    Article  CAS  Google Scholar 

  48. Boksa P . Animal models of obstetric complications in relation to schizophrenia. Brain Res Brain Res Rev 2004; 45: 1–17.

    Article  Google Scholar 

  49. Lamont RF . Recent evidence associated with the condition of preterm prelabour rupture of the membranes. Curr Opin Obstet Gynecol 2003; 15: 91–99.

    Article  Google Scholar 

  50. Rivera DL, Olister SM, Liu X, Thompson JH, Zhang XJ, Pennline K et al. Interleukin-10 attenuates experimental fetal growth restriction and demise. FASEB J 1998; 12: 189–197.

    Article  CAS  Google Scholar 

  51. Wang X, Athayde N, Trudinger B . A proinflammatory cytokine response is present in the fetal placental vasculature in placental insufficiency. Am J Obstet Gynecol 2003; 189: 1445–1451.

    Article  CAS  Google Scholar 

  52. Conrad KP, Benyo DF . Placental cytokines and the pathogenesis of preeclampsia. Am J Reprod Immunol 1997; 37: 240–249.

    Article  CAS  Google Scholar 

  53. Altshuler G . Some placental considerations related to neurodevelopmental and other disorders. J Child Neurol 1993; 8: 78–94.

    Article  CAS  Google Scholar 

  54. Gayle DA, Beloosesky R, Desai M, Amidi F, Nunez SE, Ross MG . Maternal LPS induces cytokines in the amniotic fluid and corticotropin releasing hormone in the fetal rat brain. Am J Physiol Regul Integr Comp Physiol 2004; 286: R1024–R1029.

    Article  CAS  Google Scholar 

  55. Fan J, Wojnar MM, Theodorakis M, Lang CH . Regulation of insulin-like growth factor (IGF)-I mRNA and peptide and IGF-binding proteins by interleukin-1. Am J Physiol 1996; 270 (3 Part 2): R621–R629.

    PubMed  CAS  Google Scholar 

  56. Ajo R, Cacicedo L, Navarro C, Sanchez-Franco F . Growth hormone action on proliferation and differentiation of cerebral cortical cells from fetal rat. Endocrinology 2003; 144: 1086–1097.

    Article  CAS  Google Scholar 

  57. Beishuizen A, Thijs LG . Endotoxin and the hypothalamo–pituitary–adrenal (HPA) axis. J Endotoxin Res 2003; 9: 3–24.

    PubMed  CAS  Google Scholar 

  58. Turnbull AV, Rivier CL . Regulation of the hypothalamic–pituitary–adrenal axis by cytokines: actions and mechanisms of action. Physiol Rev 1999; 79: 1–71.

    Article  CAS  Google Scholar 

  59. Dubuis JM, Dayer JM, Siegrist-Kaiser CA, Burger AG . Human recombinant interleukin-1 beta decreases plasma thyroid hormone and thyroid stimulating hormone levels in rats. Endocrinology 1988; 123: 2175–2181.

    Article  CAS  Google Scholar 

  60. Wartofsky L, Burman KD . Alterations in thyroid function in patients with systemic illness: the ‘euthyroid sick syndrome’. Endocr Rev 1982; 3: 164–217.

    Article  CAS  Google Scholar 

  61. Dupouy JP, Coffigny H, Magre S . Maternal and foetal corticosterone levels during late pregnancy in rats. J Endocrinol 1975; 65: 347–352.

    Article  CAS  Google Scholar 

  62. Zarrow MX, Philpott JE, Denenberg VH . Passage of 14C-4-corticosterone from the rat mother to the foetus and neonate. Nature 1970; 226: 1058–1059.

    Article  CAS  Google Scholar 

  63. Porterfield SP, Hendrich CE . The thyroidectomized pregnant rat – an animal model to study fetal effects of maternal hypothyroidism. Adv Exp Med Biol 1991; 299: 107–132.

    Article  CAS  Google Scholar 

  64. Matthews SG . Antenatal glucocorticoids and programming of the developing CNS. Pediatr Res 2000; 47: 291–300.

    Article  CAS  Google Scholar 

  65. Sampson D, Pickard MR, Sinha AK, Evans IM, Leonard AJ, Ekins RP . Maternal thyroid status regulates the expression of neuronal and astrocytic cytoskeletal proteins in the fetal brain. J Endocrinol 2000; 167: 439–445.

    Article  CAS  Google Scholar 

  66. Koenig JI, Kirkpatrick B, Lee P . Glucocorticoid hormones and early brain development in schizophrenia. Neuropsychopharmacology 2002; 27: 309–318.

    Article  CAS  Google Scholar 

  67. Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999; 341: 549–555.

    Article  CAS  Google Scholar 

  68. Man EB, Brown JF, Serunian SA . Maternal hypothyroxinemia: psychoneurological deficits of progeny. Ann Clin Lab Sci 1991; 21: 227–239.

    PubMed  CAS  Google Scholar 

  69. Arora KL, Cohen BJ, Beaudoin AR . Fetal and placental responses to artificially induced hyperthermia in rats. Teratology 1979; 19: 251–259.

    Article  CAS  Google Scholar 

  70. Edwards MJ, Penny RH, Zevnik I . A brain cell deficit in newborn guinea-pigs following prenatal hyperthermia. Brain Res 1971; 28: 341–345.

    Article  CAS  Google Scholar 

  71. Eastman NJ, Deleon M . The etiology of cerebral palsy. Am J Obstet Gynecol 1955; 69: 950–961.

    Article  CAS  Google Scholar 

  72. Patrick MJ . Influence of maternal renal infection on the foetus and infant. Arch Dis Child 1967; 42: 208–213.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Canadian Institutes of Health Research (CIHR), from the National Alliance for Research on Schizophrenia and Depression (NARSAD), the Canadian Psychiatric Research Foundation (CPRF) and from the National Sciences and Engineering Research Council of Canada (NSERC).

Author information

Authors and Affiliations

  1. Department of Psychiatry, McGill University, Douglas Hospital Research Centre, Montreal, QC, Canada

    H Ashdown, Y Dumont, M Ng, P Boksa & G N Luheshi

  2. National Institute for Biological Standards and Control (NIBSC), Potters Bar, Hertfordshire, UK

    S Poole

Authors
  1. H Ashdown
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y Dumont
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Ng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Poole
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P Boksa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G N Luheshi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G N Luheshi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ashdown, H., Dumont, Y., Ng, M. et al. The role of cytokines in mediating effects of prenatal infection on the fetus: implications for schizophrenia. Mol Psychiatry 11, 47–55 (2006). https://doi.org/10.1038/sj.mp.4001748

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001748

Keywords

This article is cited by

Search

Advanced search

Quick links