Divergent Trophoblast Responses to Bacterial Products Mediated by TLRs

Abstract

Intrauterine infections have been associated with pregnancy complications that are also linked with increased trophoblast apoptosis. TLRs are key components of the innate immune system which recognize conserved sequences on the surface of pathogens and trigger effector cell functions. We hypothesize that intrauterine infections may cause the excessive trophoblast cell apoptosis observed in abnormal pregnancies and that TLR may provide a mechanism of pathogenesis. In this study we describe the expression and function of TLR-2 and TLR-4 in first trimester trophoblast cells. Although ligation of TLR4 induced cytokine production by trophoblast cells, TLR-2 activation induced apoptosis. TLR-2 mediated apoptosis was dependent upon the Fas-associated death domain, the inactivation of the X-linked inhibitor of apoptosis, and the activation of caspases 8, 9, and 3. These results suggest that certain intrauterine infections may directly induce trophoblast cell death through TLR-2. Our findings provide a novel mechanism of pathogenesis for certain pregnancy complications in which there is engagement of the innate immune system.

Essential Role for IL-10 in Resistance to Lipopolysaccharide-Induced Preterm Labor in Mice

“…This response is amplified by LPS-induced uterine NK cell synthesis of IFN-␥ (47). Cytokine responses in decidual leukocytes are augmented by increased production of a range of inflammatory cytokines, including TNF-␣, IL-1, IL-6, and IL-12 in choriodecidual membranes (49) and placental trophoblast cells (50).…”

Toll-like receptor profiling of seven trophoblast cell lines warrants caution for translation to primary trophoblasts

“…Ten different human TLRs, each responding to a specific set of ligands, have been identified [4]. TLR expression and activation in primary trophoblasts [5][6][7][8][9][10] may contribute substantially to development of inflammatory pregnancy complications such as preeclampsia [11][12][13]. In Tangerås/Stødle et al [7] we demonstrated a broad functional TLR profile in primary first trimester trophoblasts, while the trophoblast cell line BeWo showed no TLR mediated cytokine response.…”

Immunity in the female sheep reproductive tract

“…TLR2 and TLR4 protein expression in human placenta is strongest on the trophoblasts that cover the peripheral chorionic villi and which constitute the immediate barrier between mother and fetus [35]. Trophoblasts can produce cytokines following TLR4 ligation, but undergo apoptosis following TLR2 ligation [1].…”

“…Chlamydial hsp60 can activate cells through ligation of TLR4 [11], whereas C. trachomatis LPS is recognised by TLR2 [23]. Activation via TLR2 but not TLR4 in human trophoblasts can lead to apoptosis in vitro [1]. If this occurs during placental infection with C. abortus, the resulting damage to the placenta could compromise the pregnancy.…”