Lactobacillus rhamnosus GR-1-Induced IL-10 Production in Human Placental Trophoblast Cells Involves Activation of JAK/STAT and MAPK Pathways

Abstract

Intrauterine infection/inflammation complicates 25% to 40% of preterm births (PTB). The human vagina is normally populated by Lactobacillus species, some of which upregulate interleukin 10 (IL-10) output in lipopolysaccharide (LPS)-treated human placental trophoblast cells. We hypothesize that a probiotic strain, L rhamnosus GR-1 exerts its anti-inflammatory effect through activation of the Janus Kinases/Signal Transducers and Activators of Transcription (JAK/STAT) and mitogen-activated protein kinase (MAPK) pathways. Placental trophoblasts from term healthy pregnancies were treated with LPS in the presence or absence of pretreatments with GR-1 supernatant and/or chemical inhibitors of the intracellular signaling pathways. Phosphorylation of STAT3 and p38 was measured by Western Blot analysis, and output of IL-10 was determined by enzyme-linked immunosorbent assay (ELISA). Phosphorylation of STAT-3 and p38 was upregulated by GR-1 supernatant alone or in combination with LPS, while IL-10 output was inhibited by both JAK and p38 inhibitors. These data provide an underlying intracellular mechanism for cytokine regulation in the human placenta by L rhamnosus GR-1 and potential prevention of infection/inflammation-mediated PTB.

IL10, TGF Beta1, and IFN Gamma Modulate Intracellular Signaling Pathways and Cytokine Production to Control Toxoplasma gondii Infection in BeWo Trophoblast Cells1

“…STAT3 phosphorylation has been shown to be essential for the survival and proliferation of human trophoblast cells from JEG-3 lineage [42]. It has been shown that supernatants of Lactobacillus rhamnosus cultures induced STAT3 phosphorylation and IL10 production in human trophoblast cells, contributing to the immunosuppression at the maternal-fetal interface [43]. Mesenchymal stem cells from rat bone marrow down-modulated the maturation of murine dendritic cells when IL10 triggered the JAK1/STAT3 signaling pathway [44].…”

Probiotics, Nuclear Receptor Signaling, and Anti-Inflammatory Pathways

“…Abnormal STAT/suppressor of cytokine signaling (SOCS) signaling has been demonstrated in CD patients [110], and probiotics are also shown to modulate the JAK-STAT signaling in human placental trophoblast cells [111]. Increasing evidence further demonstrates that metabolism, xenobiotics, and nuclear receptor signaling are involved in the action of probiotics [67, 68].…”

Lactobacillus rhamnosus GR-1 enhances NF-kappaB activation in Escherichia coli-stimulated urinary bladder cells through TLR4

“…The probiotic mechanisms are believed to include the release of antibacterial substances, biosurfactant production, disruption of biofilms and competitive exclusion [16]. Furthermore, the ability of probiotic strains to modulate immunity through NF-κB and mitogen activated protein (MAP) kinase pathways, both important in the development of innate and adaptive immunity, has been reported [17,18]. Lactobacillus rhamnosus GR-1 is a probiotic isolated from a female urethra [19] used to prevent UTI and bacterial vaginosis, and it has both immunomodulatory and antimicrobial activity [20,21].…”