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*
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814;
Maxwell Finland Laboratory for Infectious Diseases, Boston Medical Center, Boston, MA 02118;
Norwegian University of Science and Technology, Trondheim, Norway; and
Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA 02118
Down-regulation of cell surface expression of Toll-like receptor
(TLR) 4 following LPS stimulation has been suggested to underlie
endotoxin tolerance. In this study, we examined whether overexpression
of TLR2 or TLR4 would affect the ability of cells to become tolerant to
LPS or the mycobacterial components, arabinose-capped lipoarabinomannan
(LAM) and soluble tuberculosis factor (STF). To this end, Chinese
hamster ovary/CD14 cells stably transfected with a NF-
B-dependent
reporter construct, endothelial leukocyte adhesion molecule CD25 (the
3E10 clone), were engineered to overexpress either human TLR2 or TLR4.
Transfected TLRs exhibited proper signaling functions, as evidenced by
increased LPS responsiveness of 3E10/TLR4 cells and acquisition of
sensitivity to TLR2-specific ligands upon transfection of TLR2 into
TLR2-negative 3E10 cells. Pretreatment of cells with LPS, LAM, or STF
did not modulate TLR2 or TLR4 cell surface expression. Following LPS
exposure, 3E10, 3E10/TLR2, and 3E10/TLR4 cells exhibited comparable
decreases in LPS-mediated NF-B activation and mitogen-activated
protein (MAP) kinase phosphorylation. Likewise, LPS pretreatment
profoundly inhibited LPS-induced NF-B translocation in Chinese
hamster ovary cells that concomitantly overexpressed human TLR4 and
myeloid differentiation protein-2 (MD-2), but failed to modulate TLR4
or MD-2 cell surface expression. Pretreatment of 3E10/TLR2 cells with
LAM or STF decreased their NF-B responses induced by subsequent
stimulation with these substances or LPS. Conversely, prior exposure of
3E10/TLR2 cells to LPS led to hyporesponsiveness to LPS, LAM, and STF,
indicating that LPS and mycobacterial products induce cross-tolerance.
Thus, tolerance to LPS and mycobacterial components cannot be
attributed solely to a decrease in TLR/MD-2 expression levels,
suggesting inhibition of expression or function of other signaling
intermediates.
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A. E. Medvedev, A. Lentschat, L. M. Wahl, D. T. Golenbock, and S. N. Vogel Dysregulation of LPS-Induced Toll-Like Receptor 4-MyD88 Complex Formation and IL-1 Receptor-Associated Kinase 1 Activation in Endotoxin-Tolerant Cells J. Immunol., November 1, 2002; 169(9): 5209 - 5216. [Abstract] [Full Text] [PDF]
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M. L. Vandenplas, R. W. Carlson, B. S. Jeyaretnam, B. McNeill, M. H. Barton, N. Norton, T. F. Murray, and J. N. Moore Rhizobium Sin-1 Lipopolysaccharide (LPS) Prevents Enteric LPS-induced Cytokine Production J. Biol. Chem., October 25, 2002; 277(44): 41811 - 41816. [Abstract] [Full Text] [PDF]
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M. Adib-Conquy and J.-M. Cavaillon Gamma Interferon and Granulocyte/Monocyte Colony-stimulating Factor Prevent Endotoxin Tolerance in Human Monocytes by Promoting Interleukin-1 Receptor-associated Kinase Expression and Its Association to MyD88 and Not by Modulating TLR4 Expression J. Biol. Chem., July 26, 2002; 277(31): 27927 - 27934. [Abstract] [Full Text] [PDF]
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S. Sato, O. Takeuchi, T. Fujita, H. Tomizawa, K. Takeda, and S. Akira A variety of microbial components induce tolerance to lipopolysaccharide by differentially affecting MyD88-dependent and -independent pathways Int. Immunol., July 1, 2002; 14(7): 783 - 791. [Abstract] [Full Text] [PDF]
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R. Jacinto, T. Hartung, C. McCall, and L. Li Lipopolysaccharide- and Lipoteichoic Acid-Induced Tolerance and Cross-Tolerance: Distinct Alterations in IL-1 Receptor-Associated Kinase J. Immunol., June 15, 2002; 168(12): 6136 - 6141. [Abstract] [Full Text] [PDF]
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A. S. Cross Invited review: Endotoxin tolerance -- current concepts in historical perspective Innate Immunity, April 1, 2002; 8(2): 83 - 98. [PDF]
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 M. W. Hornef, T. Frisan, A. Vandewalle, S. Normark, and A. Richter-Dahlfors Toll-like Receptor 4 Resides in the Golgi Apparatus and Colocalizes with Internalized Lipopolysaccharide in Intestinal Epithelial Cells J. Exp. Med., February 25, 2002; 195(5): 559 - 570. [Abstract] [Full Text] [PDF]
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J. da Silva Correia and R. J. Ulevitch MD-2 and TLR4 N-Linked Glycosylations Are Important for a Functional Lipopolysaccharide Receptor J. Biol. Chem., January 11, 2002; 277(3): 1845 - 1854. [Abstract] [Full Text] [PDF]
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