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TNFR2 increases the sensitivity of ligand-induced activation of the p38 MAPK and NF-κB pathways and signals TRAF2 protein degradation in macrophages.
Cell Signal. 2014 Apr; 26(4):683-90.CS

Abstract

Tumour necrosis factor (p55 or p60) receptor (TNFR) 1 is the major receptor that activates pro-inflammatory signalling and induces gene expression in response to TNF. Consensus is lacking for the function of (p75 or p80) TNFR2 but experiments in mice have suggested neuro-, cardio- and osteo-protective and anti-inflammatory roles. It has been shown in various cell types to be specifically required for the induction of TNFR-associated factor-2 (TRAF2) degradation and activation of the alternative nuclear factor (NF)-kappaB pathway, and to contribute to the activation of mitogen-activated protein kinases (MAPK) and the classical NF-kappaB pathway. We have investigated the signalling functions of TNFR2 in primary human and murine macrophages. We find that in these cells TNF induces TRAF2 degradation, and this is blocked in TNFR2(-/-) macrophages. TRAF2 has been previously reported to be required for TNF-induced activation of p38 MAPK. However, TRAF2 degradation does not inhibit TNF-induced tolerance of p38 MAPK activation. Neither TNF, nor lipopolysaccharide treatment, induced activation of the alternative NF-kappaB pathway in macrophages. Activation by TNF of the p38 MAPK and NF-kappaB pathways was blocked in TNFR1(-/-) macrophages. In contrast, although TNFR2(-/-) macrophages displayed robust p38 MAPK activation and IkappaBα degradation at high concentrations of TNF, at lower doses the concentration dependence of signalling was weakened by an order of magnitude. Our results suggest that, in addition to inducing TRAF2 protein degradation, TNFR2 also plays a crucial auxiliary role to TNFR1 in sensitising macrophages for the ligand-induced activation of the p38 MAPK and classical NF-kappaB pro-inflammatory signalling pathways.

Authors+Show Affiliations

Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Road Campus, Roosevelt Drive, Headington, Oxford OX3 7FY, United Kingdom.Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Road Campus, Roosevelt Drive, Headington, Oxford OX3 7FY, United Kingdom.Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Road Campus, Roosevelt Drive, Headington, Oxford OX3 7FY, United Kingdom.Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Road Campus, Roosevelt Drive, Headington, Oxford OX3 7FY, United Kingdom.Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Road Campus, Roosevelt Drive, Headington, Oxford OX3 7FY, United Kingdom.Innovation Biopharm Discovery Unit, Biopharm R&D, GlaxoSmithKline, Cambridge CB4 0WG, United Kingdom.Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Road Campus, Roosevelt Drive, Headington, Oxford OX3 7FY, United Kingdom. Electronic address: jonathan.dean@kennedy.ox.ac.uk.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24378531

Citation

Ruspi, Gerhard, et al. "TNFR2 Increases the Sensitivity of Ligand-induced Activation of the P38 MAPK and NF-κB Pathways and Signals TRAF2 Protein Degradation in Macrophages." Cellular Signalling, vol. 26, no. 4, 2014, pp. 683-90.
Ruspi G, Schmidt EM, McCann F, et al. TNFR2 increases the sensitivity of ligand-induced activation of the p38 MAPK and NF-κB pathways and signals TRAF2 protein degradation in macrophages. Cell Signal. 2014;26(4):683-90.
Ruspi, G., Schmidt, E. M., McCann, F., Feldmann, M., Williams, R. O., Stoop, A. A., & Dean, J. L. (2014). TNFR2 increases the sensitivity of ligand-induced activation of the p38 MAPK and NF-κB pathways and signals TRAF2 protein degradation in macrophages. Cellular Signalling, 26(4), 683-90. https://doi.org/10.1016/j.cellsig.2013.12.009
Ruspi G, et al. TNFR2 Increases the Sensitivity of Ligand-induced Activation of the P38 MAPK and NF-κB Pathways and Signals TRAF2 Protein Degradation in Macrophages. Cell Signal. 2014;26(4):683-90. PubMed PMID: 24378531.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - TNFR2 increases the sensitivity of ligand-induced activation of the p38 MAPK and NF-κB pathways and signals TRAF2 protein degradation in macrophages. AU - Ruspi,Gerhard, AU - Schmidt,Emily M, AU - McCann,Fiona, AU - Feldmann,Marc, AU - Williams,Richard O, AU - Stoop,A Allart, AU - Dean,Jonathan L E, Y1 - 2013/12/27/ PY - 2013/10/29/received PY - 2013/12/19/revised PY - 2013/12/22/accepted PY - 2014/1/1/entrez PY - 2014/1/1/pubmed PY - 2014/9/25/medline KW - Macrophage KW - TNF KW - TNFR KW - TRAF2 KW - p55 KW - p75 SP - 683 EP - 90 JF - Cellular signalling JO - Cell Signal VL - 26 IS - 4 N2 - Tumour necrosis factor (p55 or p60) receptor (TNFR) 1 is the major receptor that activates pro-inflammatory signalling and induces gene expression in response to TNF. Consensus is lacking for the function of (p75 or p80) TNFR2 but experiments in mice have suggested neuro-, cardio- and osteo-protective and anti-inflammatory roles. It has been shown in various cell types to be specifically required for the induction of TNFR-associated factor-2 (TRAF2) degradation and activation of the alternative nuclear factor (NF)-kappaB pathway, and to contribute to the activation of mitogen-activated protein kinases (MAPK) and the classical NF-kappaB pathway. We have investigated the signalling functions of TNFR2 in primary human and murine macrophages. We find that in these cells TNF induces TRAF2 degradation, and this is blocked in TNFR2(-/-) macrophages. TRAF2 has been previously reported to be required for TNF-induced activation of p38 MAPK. However, TRAF2 degradation does not inhibit TNF-induced tolerance of p38 MAPK activation. Neither TNF, nor lipopolysaccharide treatment, induced activation of the alternative NF-kappaB pathway in macrophages. Activation by TNF of the p38 MAPK and NF-kappaB pathways was blocked in TNFR1(-/-) macrophages. In contrast, although TNFR2(-/-) macrophages displayed robust p38 MAPK activation and IkappaBα degradation at high concentrations of TNF, at lower doses the concentration dependence of signalling was weakened by an order of magnitude. Our results suggest that, in addition to inducing TRAF2 protein degradation, TNFR2 also plays a crucial auxiliary role to TNFR1 in sensitising macrophages for the ligand-induced activation of the p38 MAPK and classical NF-kappaB pro-inflammatory signalling pathways. SN - 1873-3913 UR - https://www.unboundmedicine.com/medline/citation/24378531/TNFR2_increases_the_sensitivity_of_ligand_induced_activation_of_the_p38_MAPK_and_NF_κB_pathways_and_signals_TRAF2_protein_degradation_in_macrophages_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0898-6568(13)00390-2 DB - PRIME DP - Unbound Medicine ER -