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*
Fearing Research Laboratory, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115;
Department of Infectious Diseases, Boston Medical Center, Boston University School of Medicine, Boston, MA 02118; and
Institute of Cancer Research and Molecular Biology, Norwegian University of Science and Technology, Trondheim, Norway
Toll-like receptors (TLRs) have recently been identified as
fundamental components of the innate immune response to bacterial
pathogens. We investigated the role of TLR signaling in immune defense
of the mucosal epithelial cells of the lower female genital tract. This
site provides first line defense against microbial pathogens while
remaining tolerant to a complex biosystem of resident microbiota.
Epithelial cells derived from normal human vagina, ectocervix, and
endocervix expressed mRNA for TLR1, -2, -3, -5, and -6. However, they
failed to express TLR4 as well as MD2, two essential components of the
receptor complex for LPS in phagocytes and endothelial cells.
Consistent with this, endocervical epithelial cells were unresponsive
to protein-free preparations of lipooligosaccharide from
Neisseria gonorrhoeae and LPS from Escherichia
coli. However, they were capable of responding to whole
Gram-negative bacteria and bacterial lysates, as demonstrated by
NF-
B activation and proinflammatory cytokine production. The
presence of soluble CD14, a high-affinity receptor for LPS and other
bacterial ligands, enhanced the sensitivity of genital tract epithelial
cells to both low and high concentrations of bacteria, suggesting that
soluble CD14 can act as a coreceptor for non-TLR4 ligands. These data
demonstrate that the response to N. gonorrhoeae and
other Gram-negative bacteria at the mucosal surface of the female
genital tract occurs in the absence of endotoxin recognition and
TLR4-mediated signaling.
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