TNFR2 increases the sensitivity of ligand-induced activation of the p38 MAPK and NF-κB pathways and signals TRAF2 protein degradation in macrophages.
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-protecti...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
2014
|
| _version_ | 1826256713847668736 |
|---|---|
| author | Ruspi, G Schmidt, E McCann, F Feldmann, M Williams, R Stoop, A Dean, J |
| author_facet | Ruspi, G Schmidt, E McCann, F Feldmann, M Williams, R Stoop, A Dean, J |
| author_sort | Ruspi, G |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T18:06:37Z |
| format | Journal article |
| id | oxford-uuid:01a5859a-82cf-46d2-86c1-2dc66954e19e |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:06:37Z |
| publishDate | 2014 |
| record_format | dspace |
| spelling | oxford-uuid:01a5859a-82cf-46d2-86c1-2dc66954e19e2022-03-26T08:36:08ZTNFR2 increases the sensitivity of ligand-induced activation of the p38 MAPK and NF-κB pathways and signals TRAF2 protein degradation in macrophages.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:01a5859a-82cf-46d2-86c1-2dc66954e19eEnglishSymplectic Elements at Oxford2014Ruspi, GSchmidt, EMcCann, FFeldmann, MWilliams, RStoop, ADean, JTumour 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. |
| spellingShingle | Ruspi, G Schmidt, E McCann, F Feldmann, M Williams, R Stoop, A Dean, J TNFR2 increases the sensitivity of ligand-induced activation of the p38 MAPK and NF-κB pathways and signals TRAF2 protein degradation in macrophages. |
| title | TNFR2 increases the sensitivity of ligand-induced activation of the p38 MAPK and NF-κB pathways and signals TRAF2 protein degradation in macrophages. |
| title_full | TNFR2 increases the sensitivity of ligand-induced activation of the p38 MAPK and NF-κB pathways and signals TRAF2 protein degradation in macrophages. |
| title_fullStr | TNFR2 increases the sensitivity of ligand-induced activation of the p38 MAPK and NF-κB pathways and signals TRAF2 protein degradation in macrophages. |
| title_full_unstemmed | TNFR2 increases the sensitivity of ligand-induced activation of the p38 MAPK and NF-κB pathways and signals TRAF2 protein degradation in macrophages. |
| title_short | TNFR2 increases the sensitivity of ligand-induced activation of the p38 MAPK and NF-κB pathways and signals TRAF2 protein degradation in macrophages. |
| title_sort | tnfr2 increases the sensitivity of ligand induced activation of the p38 mapk and nf κb pathways and signals traf2 protein degradation in macrophages |
| work_keys_str_mv | AT ruspig tnfr2increasesthesensitivityofligandinducedactivationofthep38mapkandnfkbpathwaysandsignalstraf2proteindegradationinmacrophages AT schmidte tnfr2increasesthesensitivityofligandinducedactivationofthep38mapkandnfkbpathwaysandsignalstraf2proteindegradationinmacrophages AT mccannf tnfr2increasesthesensitivityofligandinducedactivationofthep38mapkandnfkbpathwaysandsignalstraf2proteindegradationinmacrophages AT feldmannm tnfr2increasesthesensitivityofligandinducedactivationofthep38mapkandnfkbpathwaysandsignalstraf2proteindegradationinmacrophages AT williamsr tnfr2increasesthesensitivityofligandinducedactivationofthep38mapkandnfkbpathwaysandsignalstraf2proteindegradationinmacrophages AT stoopa tnfr2increasesthesensitivityofligandinducedactivationofthep38mapkandnfkbpathwaysandsignalstraf2proteindegradationinmacrophages AT deanj tnfr2increasesthesensitivityofligandinducedactivationofthep38mapkandnfkbpathwaysandsignalstraf2proteindegradationinmacrophages |