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B Signaling Pathway Components1
* Department of Microbiology and Immunology, University of Maryland, Baltimore, MD 21201;
Departments of Microbiology and Oral Biology, University of Alabama, Birmingham, AL 35294; and
Regulation of Cell Growth Laboratory, National Cancer Institute, Frederick, MD 21702
In this study, tolerance induction by preexposure of murine
macrophages to Toll-like receptor (TLR)2 and TLR4 agonists was
revisited, focusing on the major signaling components associated with
NF-
B activation. Pretreatment of macrophages with a pure TLR4
agonist (protein-free Escherichia coli (Ec) LPS) or with
TLR2 agonists (Porphyromonas gingivalis LPS or synthetic
lipoprotein Pam3Cys) led to suppression of TNF-
secretion,
IL-1R-associated kinase-1, and IB kinase (IKK) kinase
activities, c-jun N-terminal kinase, and extracellular signal-regulated
kinase phosphorylation, and to suppression of NF-B DNA binding and
transactivation upon challenge with the same agonist (TLR4 or TLR2
"homotolerance," respectively). Despite inhibited NF-B DNA
binding, increased levels of nuclear NF-B were detected in
agonist-pretreated macrophages. For all the intermediate signaling
elements, heterotolerance was weaker than TLR4 or TLR2 homotolerance
with the exception of IKK kinase activity. IKK kinase activity was
unperturbed in heterotolerance. TNF- secretion was also suppressed
in P. gingivalis LPS-pretreated, Ec LPS-challenged
cells, but not vice versa, while Pam3Cys and Ec LPS did not induce a
state of cross-tolerance at the level of TNF-. Experiments designed
to elucidate novel mechanisms of NF-B inhibition in tolerized cells
revealed the potential contribution of IB
and IB
inhibitory
proteins and the necessity of TLR4 engagement for induction of
tolerance to Toll receptor-IL-1R domain-containing adapter
protein/MyD88-adapter-like-dependent gene expression. Collectively,
these data demonstrate that induction of homotolerance affects a
broader spectrum of signaling components than in heterotolerance, with
selective modulation of specific elements within the NF-B signaling
pathway.
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A. Bafica, C. A. Scanga, O. Equils, and A. Sher The induction of Toll-like receptor tolerance enhances rather than suppresses HIV-1 gene expression in transgenic mice J. Leukoc. Biol., March 1, 2004; 75(3): 460 - 466. [Abstract] [Full Text] [PDF]
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S. R. Coats, R. A. Reife, B. W. Bainbridge, T.-T. T. Pham, and R. P. Darveau Porphyromonas gingivalis Lipopolysaccharide Antagonizes Escherichia coli Lipopolysaccharide at Toll-Like Receptor 4 in Human Endothelial Cells Infect. Immun., December 1, 2003; 71(12): 6799 - 6807. [Abstract] [Full Text] [PDF]
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Q. Li and B. J. Cherayil Role of Toll-Like Receptor 4 in Macrophage Activation and Tolerance during Salmonella enterica Serovar Typhimurium Infection Infect. Immun., September 1, 2003; 71(9): 4873 - 4882. [Abstract] [Full Text] [PDF]
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I. Sabroe, R. C. Read, M. K. B. Whyte, D. H. Dockrell, S. N. Vogel, and S. K. Dower Toll-Like Receptors in Health and Disease: Complex Questions Remain J. Immunol., August 15, 2003; 171(4): 1630 - 1635. [Full Text] [PDF]
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