Article ; Online: β(2) integrins inhibit TLR responses by regulating NF-κB pathway and p38 MAPK activation.
European journal of immunology
2013 Volume 43, Issue 3, Page(s) 779–792
Abstract: Outside-in signals from β(2) integrins require immunoreceptor tyrosine-based activation motif adapters in myeloid cells that are known to dampen TLR responses. However, the relationship between β(2) integrins and TLR regulation is unclear. Here we show ... ...
| Abstract | Outside-in signals from β(2) integrins require immunoreceptor tyrosine-based activation motif adapters in myeloid cells that are known to dampen TLR responses. However, the relationship between β(2) integrins and TLR regulation is unclear. Here we show that deficiency in β(2) integrins (Itgb2(-/-) ) causes hyperresponsiveness to TLR stimulation, demonstrating that β(2) integrins inhibit signals downstream of TLR ligation. Itgb2(-/-) macrophages and dendritic cells produced more IL-12 and IL-6 than WT cells when stimulated with TLR agonists and Itgb2(-/-) mice produced more inflammatory cytokines than WT mice when injected with LPS. TLR hypersensitivity was not the result of insufficient ABIN-3, A20, Hes-1, or IRAK-M expression, nor to changes in IL-10 production or sensitivity, though Itgb2(-/-) macrophages had reduced p38 MAPK phosphorylation after LPS treatment. Furthermore, a Cbl-b-MyD88 regulatory axis is not required for TLR inhibition in macrophages. Instead, Itgb2(-/-) macrophages presented with enhanced IκBα degradation, leading to changes in NF-κB recruitment to target promoters and elevated cytokine, chemokine, and anti-apoptotic gene transcription. Thus, β(2) integrins limit TLR signaling by inhibiting NF-κB pathway activation and promoting p38 MAPK activation, thereby fine-tuning TLR-induced inflammatory responses. |
|---|---|
| MeSH term(s) | Adaptor Proteins, Signal Transducing/metabolism ; Animals ; CD11a Antigen/metabolism ; CD11b Antigen/metabolism ; CD18 Antigens/genetics ; CD18 Antigens/metabolism ; Cysteine Endopeptidases ; Cytokines/immunology ; Cytokines/metabolism ; DNA-Binding Proteins/metabolism ; Enzyme Activation ; Intracellular Signaling Peptides and Proteins/metabolism ; Lipopolysaccharides/immunology ; Macrophages/immunology ; Macrophages/metabolism ; Mice ; Mice, Knockout ; NF-kappa B/metabolism ; Signal Transduction ; Toll-Like Receptors/metabolism ; Tumor Necrosis Factor alpha-Induced Protein 3 ; Ubiquitin-Protein Ligases/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism |
| Chemical Substances | Adaptor Proteins, Signal Transducing ; CD11a Antigen ; CD11b Antigen ; CD18 Antigens ; Cytokines ; DNA-Binding Proteins ; Intracellular Signaling Peptides and Proteins ; Lipopolysaccharides ; NF-kappa B ; Tnip2 protein, mouse ; Toll-Like Receptors ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Tumor Necrosis Factor alpha-Induced Protein 3 (EC 3.4.19.12) ; Cysteine Endopeptidases (EC 3.4.22.-) ; Tnfaip3 protein, mouse (EC 3.4.22.-) |
| Language | English |
| Publishing date | 2013-02-11 |
| Publishing country | Germany |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. |
| ZDB-ID | 120108-6 |
| ISSN | 1521-4141 ; 0014-2980 |
| ISSN (online) | 1521-4141 |
| ISSN | 0014-2980 |
| DOI | 10.1002/eji.201242550 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
Full text online
More links
Kategorien
In stock of ZB MED Cologne/Königswinter
| Zs.A 489: Show issues | Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG) |
|||
| Zs.MG 85: Show issues |
Order via subito
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.