Cytokine regulation of embryonic rat dopamine and serotonin neuronal survival in vitro

Abstract

Interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) are cytokines with pleiotropic effects in the central nervous system (CNS), including an emerging role in neurodevelopment. This study measured the effects of cytokines on the survival of tyrosine hydroxylase (TH) immunoreactive dopamine neurons from the substantia nigra (SN), and 5-hydroxytryptamine (5-HT) immunoreactive serotonin neurons from the rostral raphe (RR), using cultures from embryonic day 14 (E14) rat brain. IL-1beta, IL-6, and TNF-alpha were added to cell cultures at 1, 10 and 100 U/ml. After 3 days in vitro, TH and 5-HT neurons were counted. The survival of 5-HT neurons was significantly reduced by 20-30% at 10 U/ml of IL-6. IL-1beta and TNF-alpha at doses of 1 and 10 U/ml appeared to have a similar effect on the survival of these neurons, but this effect was not statistically significant. Comparable non-significant reductions of survival also occurred for TH neurons at the lower doses of IL-6 and TNF-alpha. In separate experiments, SN and RR cultures were exposed to the cytokines at a higher dose (1000 U/ml), causing a significant 30-40% decrease in the survival of TH neurons, but little or no change in 5-HT neuronal survival. Taken together, these results show that IL-1beta, IL-6, and TNF-alpha can affect developing monoamine neurons at physiologically relevant concentrations, and that high doses differentially inhibit the survival of TH and 5-HT neurons after short exposures.

Adult behavioral and pharmacological dysfunctions following disruption of the fetal brain balance between pro-inflammatory and IL-10-mediated anti-inflammatory signaling

“…(a) The administration of systemic AMPH (2.5 mg/kg, intraperitoneally) led to a general increase in locomotor activity, with offspring of PolyI:C-treated mothers displaying a potentiated locomotor response to the drug treatment independent of the genetic background. ANOVA of distance traveled in response to AMPH treatment yielded a significant prenatal treatment  bins interaction term (F (11,330) = 2.39; P < 0.01). Subsequent ANOVAs restricted to each of the 5-min bins further showed that prenatal PolyI:C exposure significantly enhanced the locomotor reaction to AMPH between 5 and 30 min post-injection in comparison with prenatal vehicle treatment (*P < 0.05).…”

“…38 In addition, the macrophage-specific overexpression of IL-10 also abolished the fetal brain TNF-a response to maternal immunological stimulation. TNF-a is known to have potent neurodevelopmental effects by inhibiting neuronal cell survival 11 and cortical dendrite development 12 and synergistic interactions exist between TNF-a and other proinflammatory cytokines in these processes. 12,39 Elevated fetal brain levels of TNF-a have also been implicated in the emergence of enhanced neuronal apoptosis in postnatal life.…”

“…At the cellular levels, IL-1b has been shown to be the most capable in inducing the conversion of mesencephalic progenitor cells into a dopaminergic phenotype, 10 whereas IL-6 is highly efficacious in reducing the survival of fetal brain serotonin neurons. 11 Although the underlying molecular mechanisms have yet to be identified, this clearly illustrates that the effects of cytokines on early neurodevelopmental processes crucially depend on their specificity. 41 Here, we highlight that genetically determined differences in macrophage-derived IL-10 modulates cytokine specificity in a complex biological system such as the fetal brain, which in turn may critically shape the offspring's vulnerability to distinct forms of adult behavioral and pharmacological abnormalities after prenatal immune challenge or innate immune imbalances.…”

“…9 More specifically, it has been suggested that activation of pro-inflammatory cytokines, including interleukin (IL)-1b, IL-6 and tumor necrosis factor (TNF)-a, mediate the neurodevelopmental effects of maternal infections on the offspring. This class of cytokines can modulate neuronal differentiation, 10 survival 11 and dendrite growth and complexity in vitro. 12 They may also be critically involved in the precipitation of the long-term behavioral, cognitive and pharmacological consequences of prenatal immune challenge as shown in vivo.…”

Relative Prenatal and Postnatal Maternal Contributions to Schizophrenia-Related Neurochemical Dysfunction after In Utero Immune Challenge

“…Second, experimentation in animals has confirmed that, in the absence of a specific pathogen, prenatal exposure to cytokine-releasing agents (Shi et al, 2003;Zuckerman et al, 2003;Zuckerman and Weiner, 2005;Meyer et al, 2005Meyer et al, , 2006aOzawa et al, 2006) is sufficient to induce psychopathology in later life. Third, in addition to their immunological roles (Curfs et al, 1997), pro-inflammatory cytokines have various neurodevelopmental effects (eg Ling et al, 1998;Jarskog et al, 1997;Gilmore et al, 2004). Hence, an imbalance in pro-inflammatory cytokine may trigger mal-neurodevelopment in the developing fetus and ultimately precipitate neuropathology and psychopathology in the adult offspring.…”