Progesterone-Related Immune Modulation of Pregnancy and Labor

Abstract

Pregnancy involves a complex interplay between maternal neuroendocrine and immunological systems in order to establish and sustain a growing fetus. It is thought that the uterus at pregnancy transitions from quiescent to laboring state in response to interactions between maternal and fetal systems at least partly via altered neuroendocrine signaling. Progesterone (P4) is a vital hormone in maternal reproductive tissues and immune cells during pregnancy. As such, P4 is widely used in clinical interventions to improve the chance of embryo implantation, as well as reduce the risk of miscarriage and premature labor. Here we review research to date that focus on the pathways through which P4 mediates its actions on both the maternal reproductive and immune system. We will dissect the role of P4 as a modulator of inflammation, both systemic and intrinsic to the uterus, during human pregnancy and labor.

Keywords: PIBF; immune modulation; immune response; pregnancy; progesterone.

Figure 1

Proposed mechanisms of P4-regulated gene transcription to modulate T cell function. Classically, extranuclear nuclear P4 receptors (nPR) exist in an inactive state until P4 binding, after which it forms a dimer and translocates to the nucleus to bind to P4 response element (PRE) sequences within gene promoter regions to alter their transcriptional activity. Alternatively, as a monomer, nPR-P4 acts via the Src kinase to activate the MAPK cascade. P4 bound to membrane P4 receptors (mPR) alters gene transcription regulated by second messengers (cAMP and Ca²⁺) and their associated extranuclear kinases (PKA and PKC) via the MAPK signal transduction cascade to result in phosphorylation of nuclear transcription factors (TF). Membrane-bound P4 receptors mPRs and P4 receptor membrane components (PGRMC) likely affect T cell receptor (TCR) signal transduction by modulating the activities of MAPKs through Zap70, as well as Ca²⁺ mobilization caused by phospholipase Cγ (PLCγ)-driven production of diacylglycerol (DAG) and 1,4,5-trisphosphate (IP3), which lead to modulation of pro-inflammatory gene expression and T cell activation via transcription factors NF-κB, AP-1 and NFAT. Adapted with permission from Mesiano et al. (55), and Mani et al. (94).

Figure 2

P4-dependent PIBF action on T cell differentiation and cytokine production. P4 binds to PR found in P4-sensitive γδ T cells that are activated having already interacted with fetal/paternal antigen. PIBF is subsequently released, which binds to the PIBF receptor, which is heterodimerized with the IL-4 receptor, to activate the STAT6 transcription pathway for Th2 cytokine production. On Th1 cells, PIBF acts to inhibit the STAT4 pathway by promoting SOCS-3 interaction with the IL-12R receptor to inhibit Th1 cytokine production. Adapted with permission from Shah (278).

Figure 3

Summary of the immunomodulatory effects of P4. In the periphery, P4 affects T cell activation and differentiation directly by (i) T cell activation: modulation of T cell receptor (TCR) signal transduction or (ii) Induce tolerance: inducing tolerant antigen-presenting cells (APCs) including DC that suppress T cell activation during TCR engagement, as well as indirectly via induction of Tregs that subsequently modulate T cell differentiation. (iv) Cytotoxicity: P4 can also suppress cellular cytotoxicity, predominately via PIBF to block degranulation. (v) Induce tolerance at maternal fetal interface: At the maternal fetal interface, P4 can promote placental tissue growth and invasion by inducing immune-tolerant phenotypes of macrophages, natural killer (NK) and T regulatory (Treg) cells, whilst promoting exhaustion of activated CD4 and CD8 T cells that have interacted with placental-derived fetal-paternal antigens. Migration of these tolerant leukocytes to the maternal fetal-interface are partly driven by chemoattractant molecules expressed on placental tissue.