Abstract |
Our previous studies indicated that LTβR activation mainly by T cell derived LTα₁β₂ is crucial for the control and down-regulation of intestinal inflammation. In order to dissect the cellular and molecular role of LTβR activation in the experimental model of DSS-induced intestinal inflammation, we have generated cell type-specific LTβR-deficient mice with specific ablation of LTβR expression on macrophages/neutrophils (LTβR((flox/flox))×LysM-Cre). These mice develop an exacerbated intestinal inflammation in our experimental model indicating that LTβR expression on macrophages/neutrophils is responsible for the control and down-regulation of the inflammatory reaction. These results were verified by adoptive transfer experiments of BMDM from wild-type and LTβR-deficient mice. Furthermore, transfer of activated CD4+ T cells derived from wild-type mice, but not from LTβR ligand-deficient mice attenuated the signs of intestinal inflammation. Finally, we demonstrate that LTβR activation on BMDM results in induction of TRIM30α, a negative regulator of NFκB activation. Concordantly, ablation of LTβR signaling results in the inability to induce TRIM30α expression concomitant with an increased expression of pro-inflammatory cytokines in our experimental model. Taken together, our data demonstrate that LTβR activation on macrophages by CD4+ T cell derived LTαβ controls the pro-inflammatory response by activation of a TRIM30α-dependent signaling pathway, crucial for the down-regulation of the inflammatory response in this experimental model.
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Authors | Nadin Wimmer, Barbara Huber, Anja K Wege, Nicola Barabas, Johann Röhrl, Klaus Pfeffer, Thomas Hehlgans |
Journal | Molecular immunology
(Mol Immunol)
Vol. 51
Issue 2
Pg. 128-35
(Jun 2012)
ISSN: 1872-9142 [Electronic] England |
PMID | 22437076
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2012 Elsevier Ltd. All rights reserved. |
Chemical References |
- Intracellular Signaling Peptides and Proteins
- Lymphotoxin beta Receptor
- TRIM30 alpha protein, mouse
- Dextran Sulfate
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Topics |
- Animals
- CD4-Positive T-Lymphocytes
(immunology, metabolism)
- Coculture Techniques
- Colitis
(chemically induced, immunology, metabolism)
- Dextran Sulfate
(toxicity)
- Disease Models, Animal
- Enzyme-Linked Immunosorbent Assay
- Female
- Intracellular Signaling Peptides and Proteins
(immunology, metabolism)
- Lymphotoxin beta Receptor
(immunology, metabolism)
- Macrophages
(immunology, metabolism)
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Real-Time Polymerase Chain Reaction
- Reverse Transcriptase Polymerase Chain Reaction
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