Inhibition of cell proliferation by bacterial lipopolysaccharides in TLR4-positive epithelial cells: independence of nitric oxide and cytokine release.
Phylogenetically conserved toll-like receptors (TLR) recognize "pathogen-associated molecular patterns". Upon binding of ligands, TLR initiate innate immune response in immune and most likely epithelial cells. The TLR4 isoform is considered as a lipopolysaccharide (LPS) receptor. As shown here, a rat-tongue-derived epithelial cell line RTE2 expressed TLR4 mRNA and functional protein. LPS-treated RTE2 cells responded with the transient expression of inducible nitric oxide synthase (iNOS), an effector protein of TLR4 involved in the innate immune defense of monocytes. iNOS induction occurred along a nuclear factor-kappaB (NF-kappab)-dependent pathway and correlated with the increased production of NO. Moreover, LPS and lipid A were potent inhibitors of proliferation of RTE2 cells, of mouse keratinocytes, and mouse epidermis in vivo. The inhibition depended on lipid A structure, i.e., it was related to the endotoxin activity of LPS and at least in vitro was in part mediated by NF-kappaB. C57Bl/10 ScCr mice, lacking a functional TLR4, did not respond with growth inhibition, strongly suggesting a TLR4-mediated effect. RTE2 proliferation was also inhibited by transforming growth factor beta (TGFbeta) and tumor necrosis factor alpha (TNFalpha), whereas interferon gamma (IFNgamma) was a weak inhibitor. But the growth-inhibitory effect of LPS on RTE2 cells was not mediated by TNFalpha, TGFbeta, or NO. It is concluded that besides induction of innate immune responses, LPS specifically induces growth arrest in epithelial tongue cells and keratinocytes in vitro and in mouse epidermis in a TLR4-dependent but cytokine- and NO-independent manner.
Müller-Decker
Karin
K
German Cancer Research Center, Research Project Eicosanoids and Tumor Development, Heidelberg, Germany. K.Mueller-Decker@DKFZ.de
Manegold
Gwendolin
G
Butz
Herbert
H
Hinz
Detlef E
DE
Hüttner
Dirk
D
Richter
K Hartmut
KH
Tremmel
Matthias
M
Weissflog
Rico
R
Marks
Friedrich
F
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D000078404:Epidermal Cells; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006131:Growth Inhibitors / Q000378:metabolism; D008050:Lipid A / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014059:Tongue / Q000166:cytology
D016207:Cytokines; D006131:Growth Inhibitors; D008050:Lipid A; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat