Toll-like receptor 4: a potential link between "danger signals," the innate immune system, and preeclampsia?
OBJECTIVE
Toll-like receptors (TLRs) recognize microbial ligands and host products that are released during tissue damage, the so-called "danger signals." This study was conducted to determine whether changes in TLR-4 and TLR-2 expressions can be detected in the trophoblasts at the placental bed of women with and without preeclampsia.


METHODS
Placental bed biopsy specimens were obtained from women with: (1) normal term pregnancies with and without labor (each n = 20); (2) preeclampsia who delivered preterm (n = 15); and (3) preterm labor and intact membranes with and without chorioamnionitis (each n = 15). The expression pattern of TLR-4 and TLR-2 in the trophoblasts was analyzed by double immunohistochemistry.


RESULTS
(1) The median percentage of TLR-4 positive interstitial trophoblasts was significantly higher in patients with preeclampsia than in patients with preterm labor without or with histologic chorioamnionitis (P = .0002 and P = .02, respectively). (2) The median percentage of TLR-2 positive interstitial trophoblasts was not different among the study groups (P>.05). (3) TLR-4 positive trophoblasts were also frequently immunoreactive to activated nuclear factor-kappaB, tumor necrosis factor-alpha, and M30 (a specific apoptosis antigen for trophoblast). (4) Lipopolysaccharide treatment inhibited the migration of trophoblast cell lines in vitro.


CONCLUSIONS
TLR-4 protein expression is increased in interstitial trophoblasts of patients with preeclampsia. We propose that "danger signals" at the feto-maternal interface, which are recognized by trophoblasts through TLR-4, may play a key role in the creation of a local abnormal cytokine milieu. This suggests a novel mechanism that links the activation of the innate immune system through TLR-4 and preeclampsia.
Kim
Yeon Mee
YM
Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, USA.
Romero
Roberto
R
Oh
Seo Young
SY
Kim
Chong Jai
CJ
Kilburn
Brian A
BA
Armant
D Randall
DR
Nien
Jyh Kae
JK
Gomez
Ricardo
R
Mazor
Moshe
M
Saito
Shigeru
S
Abrahams
Vikki M
VM
Mor
Gil
G
D002465:Cell Movement / Q000187:drug effects; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D010920:Placenta / Q000276:immunology / Q000502:physiology; D011225:Pre-Eclampsia / Q000276:immunology* / Q000378:metabolism; D011247:Pregnancy; D011956:Receptors, Cell Surface / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014327:Trophoblasts / Q000378:metabolism / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha