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Perinatal Endotoxemia Induces Sustained Hepatic COX-2 Expression through an NFκB-Dependent Mechanism
Sarah McKenna1, Molly Eckman, Andrew Parker
1Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colo., USA.
Insights
Neonatal exposure to endotoxemia causes sustained hepatic macrophage cyclooxygenase-2 (COX-2) expression and NFκB activity, unlike in adults. This robust innate immune response may link to preterm birth complications.
Area of Science:
- Immunology
- Neonatal research
- Infectious disease
Background:
- Perinatal infections are linked to preterm birth complications.
- The role of the immature neonatal innate immune response is unclear.
Purpose of the Study:
- To investigate if the perinatal innate immune response to endotoxemia uniquely patterns cyclooxygenase-2 (COX-2) expression.
- To determine if this pattern is NFκB-dependent.
Main Methods:
- Assessed hepatic and pulmonary COX-2 mRNA in perinatal and adult mice after endotoxemia.
- Measured hepatic NFκB activity via protein degradation and nuclear translocation.
- Determined hepatic macrophage COX-2 expression and tested NFκB inhibition.
Main Results:
- Perinatal endotoxemia induced sustained hepatic macrophage COX-2 expression and NFκB activity compared to adults.
- COX-2 expression in isolated macrophages was sensitive to NFκB inhibition.
- Inhibition of NFκB in neonatal mice reduced hepatic NFκB activity and COX-2 expression.
Conclusions:
- Neonatal endotoxemia triggers a sustained hepatic NFκB and COX-2 response, indicating a robust perinatal innate immunity.
- This sustained response may connect innate immunity to diseases complicating preterm birth.
Background:
Exposure to perinatal infection is associated with the multiple morbidities complicating preterm birth. How a relatively immature innate immune response contributes to this is unknown.
Objective:
We sought to determine if the perinatal innate immune response to endotoxemia induces a unique pattern of cyclooxygenase-2 (COX-2) expression via an NFκB-dependent mechanism.
Methods:
Hepatic and pulmonary COX-2 mRNA expression was assessed following perinatal (at embryonic days 15 and 19 and after birth) or adult endotoxemia. Hepatic NFκB activity was assessed by cytosolic inhibitory protein degradation and subunit nuclear translocation. Immunohistochemistry and isolated cell preparations determined hepatic macrophage COX-2 expression, and the effect of pharmacologic and genetic inhibition of NFκB activity was tested.
Results:
Perinatal endotoxemia induced sustained hepatic macrophage COX-2 expression and NFκB activity compared to in exposed adults. Isolated hepatic macrophages and immunohistochemistry demonstrated enriched LPS-induced COX-2 expression that was sensitive to pharmacologic and genetic approaches to attenuate NFκB activity. Finally, pharmacologic inhibition of endotoxemia-induced NFκB activity in neonatal mice prevented hepatic NFκB activity and attenuated COX-2 expression.
Conclusion:
Our findings of sustained neonatal hepatic NFκB activity and COX-2 expression in response to endotoxemia support a robust perinatal innate immune response. This may represent a link between the innate immune response and the pathogenesis of diseases associated with preterm birth.
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