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Induction of in vitro reprogramming by Toll-like receptor (TLR)2 and TLR4 agonists in murine macrophages: effects of TLR 'homotolerance' versus 'heterotolerance' on NF-kappa B signaling pathway components
- Source :
- Journal of immunology (Baltimore, Md. : 1950). 170(1)
- Publication Year :
- 2002
-
Abstract
- 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-κB 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-α secretion, IL-1R-associated kinase-1, and IκB kinase (IKK) kinase activities, c-jun N-terminal kinase, and extracellular signal-regulated kinase phosphorylation, and to suppression of NF-κB DNA binding and transactivation upon challenge with the same agonist (TLR4 or TLR2 “homotolerance,” respectively). Despite inhibited NF-κB DNA binding, increased levels of nuclear NF-κB 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-α 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-α. Experiments designed to elucidate novel mechanisms of NF-κB inhibition in tolerized cells revealed the potential contribution of IκBε and IκBξ 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-κB signaling pathway.
- Subjects :
- Lipopolysaccharides
IκB kinase
Transactivation
Mice
Immunology and Allergy
Drosophila Proteins
Cells, Cultured
Sequence Deletion
Toll-like receptor
Mice, Inbred C3H
Membrane Glycoproteins
Toll-Like Receptors
NF-kappa B
Cell biology
I-kappa B Kinase
DNA-Binding Proteins
Tolerance induction
Interleukin-1 Receptor-Associated Kinases
Female
Signal transduction
Mitogen-Activated Protein Kinases
Signal Transduction
Immunology
Down-Regulation
Receptors, Cell Surface
Biology
Protein Serine-Threonine Kinases
Cell Line
Immune Tolerance
Animals
Humans
RNA, Messenger
Kinase activity
CHUK
Protein Kinase Inhibitors
Tumor Necrosis Factor-alpha
I-Kappa-B Kinase
JNK Mitogen-Activated Protein Kinases
Transcription Factor RelA
NF-kappa B p50 Subunit
Interferon-beta
Toll-Like Receptor 2
Enzyme Activation
Mice, Inbred C57BL
Toll-Like Receptor 4
Transcription Factor AP-1
Macrophages, Peritoneal
Trans-Activators
Host Cell Factor C1
Protein Kinases
Octamer Transcription Factor-1
Transcription Factors
Subjects
Details
- ISSN :
- 00221767
- Volume :
- 170
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Accession number :
- edsair.doi.dedup.....4b469244829a661af65aa77c9e6e78d6