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Articles, Neurobiology of Disease

Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6

Stephen E. P. Smith, Jennifer Li, Krassimira Garbett, Karoly Mirnics and Paul H. Patterson
Journal of Neuroscience 3 October 2007, 27 (40) 10695-10702; https://doi.org/10.1523/JNEUROSCI.2178-07.2007
Stephen E. P. Smith
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Jennifer Li
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Krassimira Garbett
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Karoly Mirnics
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Paul H. Patterson
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    Figure 1.

    The offspring of mice given injections of recombinant IL-6 exhibit abnormal behaviors. a, Offspring of mice given injections of IL-6 but not IFNγ have a PPI deficit at a prepulse intensity of 85 dB (F(2,79) = 4.369; p < 0.05). *p < 0.05 versus control. b, PE offspring of control mice show normal LI compared with NPE animals, as do PE offspring of IFNγ-injected mothers. Offspring of IL-6-injected mothers, in contrast, do not demonstrate significant LI (F(3,103) = 10.22; p < 0.0001). *p < 0.05 versus NPE; **p < 0.001 versus NPE.

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    Figure 2.

    Abnormal behavior in MIA offspring is prevented by maternal treatment with anti-IL-6 antibody. a, Offspring of mice treated with poly(I:C) lack LI. Coinjection of anti-IL-6 with poly(I:C) restores significant LI, whereas coinjection of anti-IFNγ does not (F(4,132) = 7.566; p < 0.0001). **p < 0.001 versus NPE; *p < 0.01 versus NPE. b, Compared with controls, the offspring of mice treated with poly(I:C) show a PPI deficit at a prepulse level of 85 dB. Coinjection with anti-IL-6 prevents this deficit. The PPI of offspring of mice given coinjections of poly(I:C) and anti-IFNγ or anti-IL-1β are not significantly different from control or poly(I:C) (F(4,270) = 4.195; p < 0.005). *p < 0.001 versus control; #p < 0.05 versus poly(I:C). c, d, In the open-field test, offspring of mice treated with poly(I:C) make fewer entries than controls into the center (c) and travel less total distance (d). Offspring of mice given coinjections of anti-IL-6 enter the center as often as control mice [F(3,123) = 3.703; p < 0.05; *p < 0.05 vs control; #p < 0.05 vs poly(I:C)] and move a similar total distance [F(3,123) = 6.666; p < 0.0005; *p < 0.01 vs control; #p < 0.001 vs poly(I:C)]. Offspring of mice given coinjections of poly(I:C) and anti-IFNγ are not significantly different from controls or poly(I:C). e, Tracks recorded during the open-field session demonstrate increased thigmotaxis in offspring of poly(I:C)-treated mice compared with offspring of mice given coinjections of an IL-6 antibody. f, In the social interaction test, control mice show a strong preference for the social chamber [defined as (percentage of time in social chamber) − (percentage of time in opposite chamber)], whereas the offspring of poly(I:C)-treated mice show no such preference. Again, the deficit is corrected by maternal administration of IL-6 antibody (F(3,50) = 4.244; p < 0.01). *p < 0.05 versus control; #p < 0.05 versus poly(I:C).

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    Figure 3.

    Unsupervised clustering of microarray data show anti-IL-6 treatment rescues transcriptome changes in MIA offspring. Sixty-one genes show significant (p < 0.01) expression differences between the adult offspring of poly(I:C)-treated and saline-injected mice. Two-dimensional, unsupervised clustering of these genes (x-axis genes, y-axis samples) reveals control (Sal; blue bars), poly(I:C) (pIC; red bars), and poly(I:C) plus anti-IL-6 (pIC+aIL6; purple bars) animals cluster according to treatment, with only one pIC+aIL6 outlier. Significantly, the pIC+aIL6 animals cluster with saline-injected controls, rather than with pIC offspring. Each column represents expression values from a single animal. Genes are annotated by Affymetrix probe set/Unigene identifiers. Color intensity represents the magnitude of the gene expression change compared with the overall average intensity (green, decreased; red, increased; black, unchanged).

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The Journal of Neuroscience: 27 (40)
Journal of Neuroscience
Vol. 27, Issue 40
3 Oct 2007
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Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6
Stephen E. P. Smith, Jennifer Li, Krassimira Garbett, Karoly Mirnics, Paul H. Patterson
Journal of Neuroscience 3 October 2007, 27 (40) 10695-10702; DOI: 10.1523/JNEUROSCI.2178-07.2007

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Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6
Stephen E. P. Smith, Jennifer Li, Krassimira Garbett, Karoly Mirnics, Paul H. Patterson
Journal of Neuroscience 3 October 2007, 27 (40) 10695-10702; DOI: 10.1523/JNEUROSCI.2178-07.2007
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  • Pathogenesis of Schizophrenia & Autism: The Interaction between Interleukin & Insulin Systems
    Ganesan Venkatasubramanian
    Published on: 26 December 2007
  • Published on: (26 December 2007)
    Page navigation anchor for Pathogenesis of Schizophrenia & Autism: The Interaction between Interleukin & Insulin Systems
    Pathogenesis of Schizophrenia & Autism: The Interaction between Interleukin & Insulin Systems
    • Ganesan Venkatasubramanian, Assistant Professor of Psychiatry, National Institute of Mental Health & Neurosciences

    Sir:

    Dr. Patterson’s group has elucidated a critical finding that supports the role of interleukin-6 (IL-6) in the pathogenesis of schizophrenia and autism in the context of maternal immune activation (Smith et al 2007). Extending the three mechanisms of action by IL-6 postulated by Smith et al (2007), I hypothesize that interaction between IL-6 and insulin systems (specifically Insulin-like Growth Factor-1 [I...

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    Sir:

    Dr. Patterson’s group has elucidated a critical finding that supports the role of interleukin-6 (IL-6) in the pathogenesis of schizophrenia and autism in the context of maternal immune activation (Smith et al 2007). Extending the three mechanisms of action by IL-6 postulated by Smith et al (2007), I hypothesize that interaction between IL-6 and insulin systems (specifically Insulin-like Growth Factor-1 [IGF- 1]) might play a crucial role.

    IGF-1 plays a significant role in fetal development (Fowden, 2003). Also, IGF-1 has neuroprotective, anti-apoptotic properties that are crucial for optimal development of the brain (Dore et al 1997). Interestingly, IL-6 inhibits the secretion of IGF-I and its biological activity (de Martino et al 2000; Lazarus et al 1993). Cerebral damage in fetal pro-inflammatory states has been associated with high IL-6 and low IGF-1 levels (Hansen-Pupp et al 2007). These studies support significant interaction between IL-6 and IGF-1.

    Increased IL-6 (Potvin et al 2007) as well as deficient IGF-1 (Venkatasubramanian et al 2007) have been demonstrated in schizophrenia. Autism is also associated with higher IL-6 (Jyonouchi et al 2001) and lower IGF-1 (Riikonen et al 2006). Interestingly, maternal infection has been shown to increase the expression of fetal pro-inflammatory genes like IL-6 in the mouse (Liverman et al 2006). Hence, it is possible that maternal immune activation might result in persistent over-expression of IL-6 genes in human adolescents and adults, leading to deficient IGF-1 culminating in neurobehavioral disorders like schizophrenia and autism. In summary, this postulate of neuro-immuno-metabolic effects of IL-6 further supports the key observations reported by Smith et al (2007).

    References

    de Martino M, Galli L, Chiarelli F, Verrotti A, Rossi ME, Bindi G, Galluzzi F, Salti R, Vierucci A (2000) Interleukin-6 release by cultured peripheral blood mononuclear cells inversely correlates with height velocity, bone age, insulin-like growth factor-I, and insulin-like growth factor binding protein-3 serum levels in children with perinatal HIV-1 infection. Clin Immunol 94:212-218.

    Dore S, Kar S, Quirion R (1997) Insulin-like growth factor I protects and rescues hippocampal neurons against beta-amyloid- and human amylin- induced toxicity. Proc Natl Acad Sci U S A 94:4772–4777.

    Fowden AL (2003) The insulin-like growth factors and feto-placental growth. Placenta 24:803-812.

    Hansen-Pupp I, Hellström-Westas L, Cilio CM, Andersson S, Fellman V, Ley D (2007) Inflammation at birth and the insulin-like growth factor system in very preterm infants. Acta Paediatr 96:830-836.

    Jyonouchi H, Sun S, Le H (2001) Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression. J Neuroimmunol 120:170-179.

    Lazarus DD, Moldawer LL, Lowry SF (1993) Insulin-like growth factor-1 activity is inhibited by interleukin-1 alpha, tumor necrosis factor-alpha, and interleukin-6. Lymphokine Cytokine Res 12:219-223.

    Liverman CS, Kaftan HA, Cui L, Hersperger SG, Taboada E, Klein RM, Berman NE (2006) Altered expression of pro-inflammatory and developmental genes in the fetal brain in a mouse model of maternal infection. Neurosci Lett 399:220-225.

    Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, Kouassi E (2007) Inflammatory Cytokine Alterations in Schizophrenia: A Systematic Quantitative Review. Biol Psychiatry [Epub ahead of print]

    Riikonen R, Makkonen I, Vanhala R, Turpeinen U, Kuikka J, Kokki H (2006) Cere brospinal fluid insulin-like growth factors IGF-1 and IGF-2 in infantileautism.Dev Med Child Neurol 48:751-755.

    Smith SE, Li J, Garbett K, Mirnics K, Patterson PH (2007) Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci 27:10695-10702.

    Venkatasubramanian G, Chittiprol S, Neelakantachar N, Naveen MN, Thirthall J, Gangadhar BN, Shetty KT (2007) Insulin and insulin-like growth factor-1 abnormalities in antipsychotic-naive schizophrenia. Am J Psychiatry 164:1557-1560.

    Show Less
    Competing Interests: None declared.

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