Abstract
The mechanisms by which prenatal events affect development of adult disease are incompletely characterized. Based on findings in a murine model of maternal transmission of asthma risk, we sought to test the role of the pro-asthmatic cytokines interleukin IL-4 and -13. To assess transplacental passage of functional cytokines, we assayed phosphorylation of STAT-6, a marker of IL-4 and -13 signaling via heterodimeric receptor complexes which require an IL-4 receptor alpha subunit. IL-4 receptor alpha−/− females were mated to wild-type males, and pregnant females were injected with supraphysiologic doses of IL-4 or 13. One hour after injection, the receptor heterozygotic embryos were harvested and tissue nuclear proteins extracts assayed for phosphorylation of STAT-6 by Western blot. While direct injection of embryos produced a robust positive control, no phosphorylation was seen after maternal injection with either IL-4 or -13, indicating that neither crossed the placenta in detectable amounts. The data demonstrate a useful approach to assay for transplacental passage of functional maternal molecules, and indicate that molecules other than IL-4 and IL-13 may mediate transplacental effects in maternal transmission of asthma risk.
Highlights
Prenatal events can affect development of certain adult diseases [1,2,3,4], but the mechanisms are not clear
The aim of this study was to characterize a novel assay to assess for the transplacental passage of functional cytokines, and to use this technique to assess for passage of the pro-asthmatic/proinflammatory cytokines interleukin 4 and 13 (IL-4 and IL-13) previously implicated in maternal transmission of asthma risk [10,12]
In order to devise a functional assay to assess for transplacental passage of IL-4 and 13, we made use of IL4 receptor alpha (IL4Ra)2/2 transgenic mice and STAT-6 phosphorylation
Summary
Prenatal events can affect development of certain adult diseases [1,2,3,4], but the mechanisms are not clear. Our laboratory has developed a mouse model that recapitulates this ‘maternal effect’[10]. In this model, offspring of mother mice with ovalbumin (OVA)-induced asthma develop an asthma-like phenotype (i.e. airway hyperreactivity and airway inflammation) following an ‘intentionally suboptimal’ asthma induction protocol, whereas offspring of non-asthmatic mother mice do not. This maternal effect is allergen-independent, since offspring show increased susceptibility to other allergens besides OVA. This suggests a role for mediators with broad effects, e.g., cytokines, rather specific antibodies
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