Tumour necrosis factor alpha promotes secretion of 14-3-3? by inducing necroptosis in macrophages
Background 14-3-3? is an intracellular protein also detected in the serum and synovial fluid of patients with rheumatoid arthritis (RA). It is closely related to disease activity and anti-cyclic citrullinated peptide antibody levels. However, the main source of 14-3-3? and the mechanism of its relea...
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| Veröffentlicht in: | Arthritis research & therapy 2020-02, Vol.22 (1) |
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| creator | Trimova, Gulzhan Yamagata, Kaoru Iwata, Shigeru Hirata, Shintaro Zhang, Tong Uemura, Fumi Satoh, Minoru Biln, Norma Nakayamada, Shingo Maksymowych, Walter P Tanaka, Yoshiya |
| description | Background 14-3-3? is an intracellular protein also detected in the serum and synovial fluid of patients with rheumatoid arthritis (RA). It is closely related to disease activity and anti-cyclic citrullinated peptide antibody levels. However, the main source of 14-3-3? and the mechanism of its release into the extracellular space remain unclear. Addressing these two points was the main goal of the current study. Methods The source of 14-3-3? was investigated by immunostaining RA synovial tissue. Fibroblast-like synoviocytes, CD4.sup.+ cells, and macrophages were selected as candidates among the various cell types in the synovial tissue. Phosphorylation of mixed-lineage kinase domain-like pseudokinase (MLKL) and cell death of macrophages were studied by phalloidin staining and electron microscopy after stimulation with an oxidative stress inducer (diamide) or tumour necrosis factor (TNF)-[alpha]. Extracellular 14-3-3? protein levels were examined by western blotting. Results Macrophages from the synovial tissue from RA, but not osteoarthritis, showed dense and widespread cytoplasmic staining for the 14-3-3? protein, co-localized with peptidylarginine deiminase 4. Swelling and membrane rupture of macrophages were induced by treatment with TNF-[alpha], but not interleukin (IL) 6/soluble IL-6 receptor (sIL-6R). Increased MLKL phosphorylation followed by necroptosis was also induced in TNF-[alpha]-stimulated macrophages. Necrostatin-1, a necroptosis inhibitor, antagonized MLKL phosphorylation. High levels of 14-3-3? were detected in the culture supernatants of macrophages stimulated with diamide and TNF-[alpha], but not IL-6/sIL-6R. Conclusions Macrophages that highly express 14-3-3? undergo TNF-[alpha]-induced necroptosis with damage to the cellular structure, resulting in the secretion of 14-3-3? into the extracellular space. The current study provides a novel mechanism for 14-3-3? level increase in the RA synovial fluid. Keywords: Rheumatoid arthritis, 14-3-3?, TNF-[alpha], Necroptosis, Macrophage |
| doi_str_mv | 10.1186/s13075-020-2110-9 |
| format | Article |
| fullrecord | <record><control><sourceid>gale</sourceid><recordid>TN_cdi_gale_infotracmisc_A616402195</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A616402195</galeid><sourcerecordid>A616402195</sourcerecordid><originalsourceid>FETCH-LOGICAL-g675-e67cb1e556c5e48230fc031d3c1e0d2c70d9bf162cb88418ea50e8a7cec506e83</originalsourceid><addsrcrecordid>eNptjjtPwzAQxz2ARCl8ADZLzC4-v-JMqKp4SZVYuleOc06NGruKk4FvT6AMDOiG0_0fPx0hd8BXANY8FJC80owLzgQAZ_UFWYCqLDNSqytyXcoH50LUQi2I2019ngaa0A-5xEKD82MeqDueDo6ehtznEQsts41jzInmQEExyeQjbT5pTO3kY-rO_dP4g4iJ9u77PLgOyw25DO5Y8PZ3L8nu-Wm3eWXb95e3zXrLOjM_i6byDaDWxmtUVkgePJfQSg_IW-Er3tZNACN8Y60Ci05ztK7y6DU3aOWS3J-xnTviPqaQx8H5Pha_Xxswiguo9Zxa_ZOap8U--pwwxFn_U_gCcLxkxg</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Tumour necrosis factor alpha promotes secretion of 14-3-3? by inducing necroptosis in macrophages</title><source>DOAJ Directory of Open Access Journals</source><source>PubMed Central Open Access</source><source>Springer Nature OA Free Journals</source><source>PubMed Central</source><source>SpringerLink Journals - AutoHoldings</source><creator>Trimova, Gulzhan ; Yamagata, Kaoru ; Iwata, Shigeru ; Hirata, Shintaro ; Zhang, Tong ; Uemura, Fumi ; Satoh, Minoru ; Biln, Norma ; Nakayamada, Shingo ; Maksymowych, Walter P ; Tanaka, Yoshiya</creator><creatorcontrib>Trimova, Gulzhan ; Yamagata, Kaoru ; Iwata, Shigeru ; Hirata, Shintaro ; Zhang, Tong ; Uemura, Fumi ; Satoh, Minoru ; Biln, Norma ; Nakayamada, Shingo ; Maksymowych, Walter P ; Tanaka, Yoshiya</creatorcontrib><description>Background 14-3-3? is an intracellular protein also detected in the serum and synovial fluid of patients with rheumatoid arthritis (RA). It is closely related to disease activity and anti-cyclic citrullinated peptide antibody levels. However, the main source of 14-3-3? and the mechanism of its release into the extracellular space remain unclear. Addressing these two points was the main goal of the current study. Methods The source of 14-3-3? was investigated by immunostaining RA synovial tissue. Fibroblast-like synoviocytes, CD4.sup.+ cells, and macrophages were selected as candidates among the various cell types in the synovial tissue. Phosphorylation of mixed-lineage kinase domain-like pseudokinase (MLKL) and cell death of macrophages were studied by phalloidin staining and electron microscopy after stimulation with an oxidative stress inducer (diamide) or tumour necrosis factor (TNF)-[alpha]. Extracellular 14-3-3? protein levels were examined by western blotting. Results Macrophages from the synovial tissue from RA, but not osteoarthritis, showed dense and widespread cytoplasmic staining for the 14-3-3? protein, co-localized with peptidylarginine deiminase 4. Swelling and membrane rupture of macrophages were induced by treatment with TNF-[alpha], but not interleukin (IL) 6/soluble IL-6 receptor (sIL-6R). Increased MLKL phosphorylation followed by necroptosis was also induced in TNF-[alpha]-stimulated macrophages. Necrostatin-1, a necroptosis inhibitor, antagonized MLKL phosphorylation. High levels of 14-3-3? were detected in the culture supernatants of macrophages stimulated with diamide and TNF-[alpha], but not IL-6/sIL-6R. Conclusions Macrophages that highly express 14-3-3? undergo TNF-[alpha]-induced necroptosis with damage to the cellular structure, resulting in the secretion of 14-3-3? into the extracellular space. The current study provides a novel mechanism for 14-3-3? level increase in the RA synovial fluid. Keywords: Rheumatoid arthritis, 14-3-3?, TNF-[alpha], Necroptosis, Macrophage</description><identifier>ISSN: 1478-6354</identifier><identifier>DOI: 10.1186/s13075-020-2110-9</identifier><language>eng</language><publisher>BioMed Central Ltd</publisher><subject>Antibodies ; Arthritis ; Beef cattle ; Cell death ; Diagnosis ; Diseases ; Electron microscopy ; Health aspects ; Interleukins ; Macrophages ; Microscopy ; Necrosis ; Novels ; Osteoarthritis ; Oxidative stress ; Peptides ; Rheumatoid factor ; Tumor necrosis factor ; Tumors</subject><ispartof>Arthritis research & therapy, 2020-02, Vol.22 (1)</ispartof><rights>COPYRIGHT 2020 BioMed Central Ltd.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,864,27924,27925</link.rule.ids></links><search><creatorcontrib>Trimova, Gulzhan</creatorcontrib><creatorcontrib>Yamagata, Kaoru</creatorcontrib><creatorcontrib>Iwata, Shigeru</creatorcontrib><creatorcontrib>Hirata, Shintaro</creatorcontrib><creatorcontrib>Zhang, Tong</creatorcontrib><creatorcontrib>Uemura, Fumi</creatorcontrib><creatorcontrib>Satoh, Minoru</creatorcontrib><creatorcontrib>Biln, Norma</creatorcontrib><creatorcontrib>Nakayamada, Shingo</creatorcontrib><creatorcontrib>Maksymowych, Walter P</creatorcontrib><creatorcontrib>Tanaka, Yoshiya</creatorcontrib><title>Tumour necrosis factor alpha promotes secretion of 14-3-3? by inducing necroptosis in macrophages</title><title>Arthritis research & therapy</title><description>Background 14-3-3? is an intracellular protein also detected in the serum and synovial fluid of patients with rheumatoid arthritis (RA). It is closely related to disease activity and anti-cyclic citrullinated peptide antibody levels. However, the main source of 14-3-3? and the mechanism of its release into the extracellular space remain unclear. Addressing these two points was the main goal of the current study. Methods The source of 14-3-3? was investigated by immunostaining RA synovial tissue. Fibroblast-like synoviocytes, CD4.sup.+ cells, and macrophages were selected as candidates among the various cell types in the synovial tissue. Phosphorylation of mixed-lineage kinase domain-like pseudokinase (MLKL) and cell death of macrophages were studied by phalloidin staining and electron microscopy after stimulation with an oxidative stress inducer (diamide) or tumour necrosis factor (TNF)-[alpha]. Extracellular 14-3-3? protein levels were examined by western blotting. Results Macrophages from the synovial tissue from RA, but not osteoarthritis, showed dense and widespread cytoplasmic staining for the 14-3-3? protein, co-localized with peptidylarginine deiminase 4. Swelling and membrane rupture of macrophages were induced by treatment with TNF-[alpha], but not interleukin (IL) 6/soluble IL-6 receptor (sIL-6R). Increased MLKL phosphorylation followed by necroptosis was also induced in TNF-[alpha]-stimulated macrophages. Necrostatin-1, a necroptosis inhibitor, antagonized MLKL phosphorylation. High levels of 14-3-3? were detected in the culture supernatants of macrophages stimulated with diamide and TNF-[alpha], but not IL-6/sIL-6R. Conclusions Macrophages that highly express 14-3-3? undergo TNF-[alpha]-induced necroptosis with damage to the cellular structure, resulting in the secretion of 14-3-3? into the extracellular space. The current study provides a novel mechanism for 14-3-3? level increase in the RA synovial fluid. Keywords: Rheumatoid arthritis, 14-3-3?, TNF-[alpha], Necroptosis, Macrophage</description><subject>Antibodies</subject><subject>Arthritis</subject><subject>Beef cattle</subject><subject>Cell death</subject><subject>Diagnosis</subject><subject>Diseases</subject><subject>Electron microscopy</subject><subject>Health aspects</subject><subject>Interleukins</subject><subject>Macrophages</subject><subject>Microscopy</subject><subject>Necrosis</subject><subject>Novels</subject><subject>Osteoarthritis</subject><subject>Oxidative stress</subject><subject>Peptides</subject><subject>Rheumatoid factor</subject><subject>Tumor necrosis factor</subject><subject>Tumors</subject><issn>1478-6354</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid/><recordid>eNptjjtPwzAQxz2ARCl8ADZLzC4-v-JMqKp4SZVYuleOc06NGruKk4FvT6AMDOiG0_0fPx0hd8BXANY8FJC80owLzgQAZ_UFWYCqLDNSqytyXcoH50LUQi2I2019ngaa0A-5xEKD82MeqDueDo6ehtznEQsts41jzInmQEExyeQjbT5pTO3kY-rO_dP4g4iJ9u77PLgOyw25DO5Y8PZ3L8nu-Wm3eWXb95e3zXrLOjM_i6byDaDWxmtUVkgePJfQSg_IW-Er3tZNACN8Y60Ci05ztK7y6DU3aOWS3J-xnTviPqaQx8H5Pha_Xxswiguo9Zxa_ZOap8U--pwwxFn_U_gCcLxkxg</recordid><startdate>20200212</startdate><enddate>20200212</enddate><creator>Trimova, Gulzhan</creator><creator>Yamagata, Kaoru</creator><creator>Iwata, Shigeru</creator><creator>Hirata, Shintaro</creator><creator>Zhang, Tong</creator><creator>Uemura, Fumi</creator><creator>Satoh, Minoru</creator><creator>Biln, Norma</creator><creator>Nakayamada, Shingo</creator><creator>Maksymowych, Walter P</creator><creator>Tanaka, Yoshiya</creator><general>BioMed Central Ltd</general><scope/></search><sort><creationdate>20200212</creationdate><title>Tumour necrosis factor alpha promotes secretion of 14-3-3? by inducing necroptosis in macrophages</title><author>Trimova, Gulzhan ; Yamagata, Kaoru ; Iwata, Shigeru ; Hirata, Shintaro ; Zhang, Tong ; Uemura, Fumi ; Satoh, Minoru ; Biln, Norma ; Nakayamada, Shingo ; Maksymowych, Walter P ; Tanaka, Yoshiya</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-g675-e67cb1e556c5e48230fc031d3c1e0d2c70d9bf162cb88418ea50e8a7cec506e83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Antibodies</topic><topic>Arthritis</topic><topic>Beef cattle</topic><topic>Cell death</topic><topic>Diagnosis</topic><topic>Diseases</topic><topic>Electron microscopy</topic><topic>Health aspects</topic><topic>Interleukins</topic><topic>Macrophages</topic><topic>Microscopy</topic><topic>Necrosis</topic><topic>Novels</topic><topic>Osteoarthritis</topic><topic>Oxidative stress</topic><topic>Peptides</topic><topic>Rheumatoid factor</topic><topic>Tumor necrosis factor</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Trimova, Gulzhan</creatorcontrib><creatorcontrib>Yamagata, Kaoru</creatorcontrib><creatorcontrib>Iwata, Shigeru</creatorcontrib><creatorcontrib>Hirata, Shintaro</creatorcontrib><creatorcontrib>Zhang, Tong</creatorcontrib><creatorcontrib>Uemura, Fumi</creatorcontrib><creatorcontrib>Satoh, Minoru</creatorcontrib><creatorcontrib>Biln, Norma</creatorcontrib><creatorcontrib>Nakayamada, Shingo</creatorcontrib><creatorcontrib>Maksymowych, Walter P</creatorcontrib><creatorcontrib>Tanaka, Yoshiya</creatorcontrib><jtitle>Arthritis research & therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Trimova, Gulzhan</au><au>Yamagata, Kaoru</au><au>Iwata, Shigeru</au><au>Hirata, Shintaro</au><au>Zhang, Tong</au><au>Uemura, Fumi</au><au>Satoh, Minoru</au><au>Biln, Norma</au><au>Nakayamada, Shingo</au><au>Maksymowych, Walter P</au><au>Tanaka, Yoshiya</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tumour necrosis factor alpha promotes secretion of 14-3-3? by inducing necroptosis in macrophages</atitle><jtitle>Arthritis research & therapy</jtitle><date>2020-02-12</date><risdate>2020</risdate><volume>22</volume><issue>1</issue><issn>1478-6354</issn><abstract>Background 14-3-3? is an intracellular protein also detected in the serum and synovial fluid of patients with rheumatoid arthritis (RA). It is closely related to disease activity and anti-cyclic citrullinated peptide antibody levels. However, the main source of 14-3-3? and the mechanism of its release into the extracellular space remain unclear. Addressing these two points was the main goal of the current study. Methods The source of 14-3-3? was investigated by immunostaining RA synovial tissue. Fibroblast-like synoviocytes, CD4.sup.+ cells, and macrophages were selected as candidates among the various cell types in the synovial tissue. Phosphorylation of mixed-lineage kinase domain-like pseudokinase (MLKL) and cell death of macrophages were studied by phalloidin staining and electron microscopy after stimulation with an oxidative stress inducer (diamide) or tumour necrosis factor (TNF)-[alpha]. Extracellular 14-3-3? protein levels were examined by western blotting. Results Macrophages from the synovial tissue from RA, but not osteoarthritis, showed dense and widespread cytoplasmic staining for the 14-3-3? protein, co-localized with peptidylarginine deiminase 4. Swelling and membrane rupture of macrophages were induced by treatment with TNF-[alpha], but not interleukin (IL) 6/soluble IL-6 receptor (sIL-6R). Increased MLKL phosphorylation followed by necroptosis was also induced in TNF-[alpha]-stimulated macrophages. Necrostatin-1, a necroptosis inhibitor, antagonized MLKL phosphorylation. High levels of 14-3-3? were detected in the culture supernatants of macrophages stimulated with diamide and TNF-[alpha], but not IL-6/sIL-6R. Conclusions Macrophages that highly express 14-3-3? undergo TNF-[alpha]-induced necroptosis with damage to the cellular structure, resulting in the secretion of 14-3-3? into the extracellular space. The current study provides a novel mechanism for 14-3-3? level increase in the RA synovial fluid. Keywords: Rheumatoid arthritis, 14-3-3?, TNF-[alpha], Necroptosis, Macrophage</abstract><pub>BioMed Central Ltd</pub><doi>10.1186/s13075-020-2110-9</doi></addata></record> |
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| subjects | Antibodies Arthritis Beef cattle Cell death Diagnosis Diseases Electron microscopy Health aspects Interleukins Macrophages Microscopy Necrosis Novels Osteoarthritis Oxidative stress Peptides Rheumatoid factor Tumor necrosis factor Tumors |
| title | Tumour necrosis factor alpha promotes secretion of 14-3-3? by inducing necroptosis in macrophages |
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