(151) Interferon Beta Upregulates the Expression of the Contraction Associated Protein Cyclooxygenase-2 in a Mouse Model

An increase in uterine contractions is believed play an essential role in the pathogenesis of preterm birth. Previously, we have shown Interferon Beta (IFN-β) is a key mediator in cervical remodeling and preterm birth. However, it is unknown if IFN-β impacts pathways in the uterus associated with the regulation of contraction associated proteins, pro-inflammatory cytokines, matrix metallopeptidases (MMPs), and tissue inhibitor metallopeptidases (TIMPs). Therefore, we performed a series of animal experiments to assess the impact IFN-β may have on uterine pathways associated with preterm birth.    

Study Design:

Pregnant CD-1 mice on gestational day 17 received either an intrauterine injection of IFN-β or vehicle control. Additional experiments were performed utilizing either an intrauterine injection of Lipopolysaccharide (LPS) along with Replens vaginally, which has been shown to inhibit the expression of IFN-β, or LPS along with an anti-mouse interferon receptor (IFNaR) antibody. The uteri were collected for molecular analysis.  

Results: Treatment with an intrauterine injection of IFN-β increased the expression of the contraction associated proteins COX2 (p < 0.01), CX43 (p < 0.005), and OXTR (p < 0.001) compared to control mice. Mice receiving an intrauterine injection of LPS resulted in an increased expression of COX2 (p < 0.0001) which was decreased with Replens (p < 0.01). Treatment with Replens also decreased the expression of IL6 (p < 0.01), TNFα (p < 0.0001), IL-1β (p < 0.01), and GM-CSF (p < 0.01) as well as the ratio of MMP2:TIMP2 (p < 0.001) and MMP2:TIMP3 (p < 0.0001).   Lastly, mice treated with LPS and IFNaR had a decreased expression of COX2 (p < 0.05) compared to control mice. 

Conclusion:

These studies demonstrate INF-β is a key mediator in the expression of the contraction associated COX2 in the uterus. In addition, treatment with Replens decreased the expression of several pro-inflammatory cytokines in the uterus. By increasing our understanding of the pro-inflammatory molecular pathways in the uterus, we may be able to develop future therapies to prevent preterm birth and reduce neonatal morbidity.