Little is known regarding the maternal brain immune system during pregnancy, and its ability to respond to inflammation under this unique hormonal environment. Among mothers who received vaginal progesterone during pregnancy, the OPPTIMUM study reported a reduction in neonatal brain injuries on cerebral ultrasound scanning. In adults, progesterone reduces neuroinflammation, oxidative stress, and brain damage following traumatic brain injury. Several studies have shown that progesterone may repress NF-κβ and pro-inflammatory cytokine synthesis, such as TNF-α. As inflammation represents a putative mechanism for preterm labor, anti-inflammatory properties may be intrinsic to progesterone prevention of preterm birth. Natural progesterone was chosen for this study because natural progesterone but not 17α-OHPC has been shown to have anti-inflammatory effects at the murine maternal-fetal interface. Micronized progesterone has been shown to be effective for women with short cervical length.
17α-OHPC has been shown to be effective in preventing PTB in pregnant women with a history of PTB. There are two types of progesterone currently used for prevention of preterm birth: (1) weekly intramuscular injections of 17α-OHPC and (2) daily administration of natural micronized progesterone. Progesterone supplementation is recommended by the American College of Obstetrics and Gynecology for prevention of preterm birth in select populations. Progesterone is a pivotal hormone in pregnancy, as it maintains uterine quiescence. Consistent with immune suppression, during pregnancy, a portion of women with cell-mediated autoimmune diseases ( e.g., multiple sclerosis) evidence reduced symptoms, especially during the third trimester. Immune imbalance during pregnancy may contribute to pathological conditions such as preeclampsia, recurrent spontaneous abortion, and intrauterine growth restriction. Maintenance of pregnancy represents a challenge for the maternal immune system since it has to defend against pathogens while tolerating paternal alloantigens expressed in fetal and placental tissues. Pregnancy represents a unique immune tolerance. Our results suggest that endogenous progesterone during pregnancy may protect the brain from LPS-induced inflammation.
In NP mice, progesterone attenuated the increase in brain IMC following LPS administration. Progesterone attenuates brain inflammatory response to LPS in both NP and P mice although it has no effect on systemic inflammation. LPS significantly increased the microglial activity in both NP and P groups, which was attenuated by progesterone. In P mice, neither LPS nor LPS + progesterone altered the brain IMC population.
In the NP brains, LPS significantly increased IMC population and progesterone reduced the IMC phenotype to levels similar to controls. In both NP and P groups, progesterone significantly attenuated LPS-induced increase of nNOS and NF-kB, however with no effect on serum IL-6. LPS significantly increased brain nNOS, NF-kB, and IL-6 in both NP and P mice, with significantly greater responses in P mice. Mice were sacrificed on day 16 and maternal serum analyzed for IL-6 levels and brains analyzed for nNOS, NF-kB, IL-6 protein levels and for immature myeloid cells (IMCs) and microglial activity. On days 15 and 16, LPS/saline was administered by intraperitoneal injection (Replens + saline n = 3 Replens + LPS n = 3 progesterone + LPS n = 3). Pregnant (P: n = 9) and non-pregnant mice (NP: n = 9) were randomized to pretreatment with vaginal progesterone/carrier (Replens), daily from days 13 to 16. We sought to determine the maternal brain immune response to LPS-induced inflammation in pregnant and non-pregnant mice and whether additional progesterone supplementation attenuates this response. Progesterone has been shown to regulate immunity during pregnancy, and progesterone administration may reduce inflammation-induced preterm labor.
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