Human Fetal Membranes Generate Distinct Cytokine Profiles in Response to Bacterial Toll-Like Receptor and Nod-Like Receptor Agonists1

Abstract

Bacterial infection-associated inflammation is thought to be a major cause of preterm premature rupture of membranes. Proinflammatory cytokines, such as interleukin 1B (IL1B), can weaken fetal membranes (FM) by upregulating matrix metalloproteinases and inducing apoptosis. The mechanism by which infection leads to inflammation at the maternal-fetal interface and subsequent preterm birth is thought to involve innate immune pattern recognition receptors (PRR), such as the Toll-like receptors (TLR) and Nod-like receptors (NLR), which recognize pathogen-associated molecular patterns (PAMPs). The objective of this study was to determine the cytokine profile generated by FMs in response to the bacterial TLR and NLR agonists peptidoglycan (PDG; TLR2), lipopolysaccharide (LPS; TLR4), flagellin (TLR5), CpG ODN (TLR9), iE-DAP (Nod1), and MDP (Nod2). PDG, LPS, flagellin, iE-DAP, and MDP triggered FMs to generate an inflammatory response, but the cytokine profiles were distinct for each TLR and NLR agonist, and only IL1B and RANTES were commonly upregulated in response to all five PAMPs. CpG ODN, in contrast, had a mild stimulatory effect only on MCP-1 and primarily downregulated basal FM cytokine production. IL1B secretion induced by PDG, LPS, flagellin, iE-DAP, and MDP was associated with its processing. Furthermore, FM IL1B secretion in response to TLR2, TLR4, and TLR5 activation was caspase 1-dependent, whereas Nod1 and Nod2 induced IL1B secretion independent of caspase 1. These findings demonstrate that FMs respond to different bacterial TLR and NLR PAMPs by generating distinct inflammatory cytokine profiles through distinct mechanisms that are specific to the innate immune PRR activated.

Activation of AMPK in human fetal membranes alleviates infection-induced expression of pro-inflammatory and pro-labour mediators

“…TLR signalling is a key mechanism in infection-associated inflammation which can cause PPROM and subsequent preterm birth [10]. Up-regulation of TLRs have been reported in fetal membranes after spontaneous term labour compared to no labour [56], and with chorioamnionitis versus non-infected [57].…”

“…Bacterial infection by flagellin is a known inducer of proinflammatory and pro-labour mediators in human fetal membranes [10,22]. The effect of AMPK activators on flagellinstimulated pro-inflammatory cytokines is demonstrated in Fig.…”

“…Pathogenic microorganisms can trigger the inflammatory response via activation of Toll-like receptors (TLRs) [9], which are highly expressed at the maternal-fetal interface. Such pathogenic organisms include lipopolysaccharide (LPS; ligand to TLR4), flagellin (TLR5) and the viral dsRNA analogue poly(I:C) (TLR3), which are known to stimulate the production of cytokines and metalloproteinase (MMP)-9 in fetal membranes in the context of infection-mediated preterm labour [10].…”

Prevention of preterm birth: Harnessing science to address the global epidemic

“…Bacterial products interact with the receptors for pathogen-associated molecular patterns, such as Toll-like receptors (TLRs; mainly TLR-2 and -4) and NOD (nucleotide-binding oligomerization domain)-like receptors (NLRs), leading to tumor necrosis factor-a (TNFa)-mediated release of cytokines (such as IL-1 and IL-6) and chemokines (such as IL-8 and RANTES), the production of other proinflammatory mediators, and apoptosis (46). These cytokines stimulate uterine contractions through the production of prostaglandins, primarily by the amnion and decidua, and through stimulation of fetal or maternal neutrophils (47,48).…”

Cigarette Smoke Modulates NOD1 Signal Pathway and Human ß Defensins Expression in Human Oral Mucosa

“…Treatment of Leuk-1 cells with iE-DAP (NOD1 specific agonist) was performed as previously described [20,21]. Leuk-1 cells (prepared as detailed above) were pretreated for 24 h with the presence of 50 μg/ml iE-DAP or 50 μg/ml iE-Lys.…”