IL6/sIL6R regulates TNFα-inflammatory response in synovial fibroblasts through modulation of transcriptional and post-transcriptional mechanisms
Introduction The clinical efficacy of specific interleukin-6 inhibitors has confirmed the central role of IL6 in rheumatoid arthritis (RA). However the local role of IL6, in particular in synovial fibroblasts (SF) as a direct cellular target to IL6/sIL6R signal is not well characterized. The purpose...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Valin, Alvaro [verfasserIn] Del Rey, Manuel J. [verfasserIn] Municio, Cristina [verfasserIn] Usategui, Alicia [verfasserIn] Romero, Marina [verfasserIn] Fernández-Felipe, Jesús [verfasserIn] Cañete, Juan D. [verfasserIn] Blanco, Francisco J. [verfasserIn] Ruano, Yolanda [verfasserIn] Criado, Gabriel [verfasserIn] Pablos, José L. [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2020 |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
Enthalten in: BMC cell biology - London : BioMed Central, 2000, 21(2020), 1 vom: 30. Okt. |
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| Übergeordnetes Werk: |
volume:21 ; year:2020 ; number:1 ; day:30 ; month:10 |
| Links: |
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| DOI / URN: |
10.1186/s12860-020-00317-7 |
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| Katalog-ID: |
SPR041708989 |
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| 245 | 1 | 0 | |a IL6/sIL6R regulates TNFα-inflammatory response in synovial fibroblasts through modulation of transcriptional and post-transcriptional mechanisms |
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| 520 | |a Introduction The clinical efficacy of specific interleukin-6 inhibitors has confirmed the central role of IL6 in rheumatoid arthritis (RA). However the local role of IL6, in particular in synovial fibroblasts (SF) as a direct cellular target to IL6/sIL6R signal is not well characterized. The purpose of the study was to characterize the crosstalk between TNFα and IL6/sIL6R signaling to the effector pro-inflammatory response of SF. Methods SF lines were stimulated with either TNFα, IL6/sIL6R, or both together, for the time and dose indicated for each experiment, and where indicated, cells were treated with inhibitors actinomycin D, adalimumab, ruxolitinib and cycloheximide. mRNA expression of cytokines, chemokines and matrix metalloproteases (MMPs) were analyzed by quantitative RT-PCR. Level of IL8/CXCL8 and CCL8 in culture supernatants was measured by ELISA. Mononuclear and polymorphonuclear cells migration assays were assessed by transwell using conditioned medium from SF cultures. Statistical analyses were performed as indicated in the corresponding figure legends and a p-value < 0.05 was considered statistically significant. Results The stimulation of SF with IL6/sIL6R and TNFα, cooperatively promotes the expression of mono- and lymphocytic chemokines such as IL6, CCL8 and CCL2, as well as matrix degrading enzymes such as MMP1, while inhibiting the induction of central neutrophil chemokines such as IL8/CXCL8. These changes in the pattern of chemokines expression resulted in reduced polymorphonuclear (PMN) and increased mononuclear cells (MNC) chemoattraction by SF. Mechanistic analyses of the temporal expression of genes demonstrated that the cooperative regulation mediated by these two factors is mostly induced through de novo transcriptional mechanisms activated by IL6/sIL6R. Furthermore, we also demonstrate that TNFα and IL6/sIL6R cooperation is partially mediated by the expression of secondary factors signaling through JAK/STAT pathways. Conclusions These results point out to a highly orchestrated response to IL6 in TNFα-induced SF and provide additional insights into the role of IL6/sIL6R in the context of RA, highlighting the contribution of IL6/sIL6R to the interplay of SF with other inflammatory cells. | ||
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| 650 | 4 | |a Synovial fibroblast |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Inflammatory response |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Rheumatoid arthritis |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Cross-talk |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Transcriptional mechanisms |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Post-transcriptional mechanisms |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a JAK/STAT |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Del Rey, Manuel J. |e verfasserin |4 aut | |
| 700 | 1 | |a Municio, Cristina |e verfasserin |4 aut | |
| 700 | 1 | |a Usategui, Alicia |e verfasserin |4 aut | |
| 700 | 1 | |a Romero, Marina |e verfasserin |4 aut | |
| 700 | 1 | |a Fernández-Felipe, Jesús |e verfasserin |4 aut | |
| 700 | 1 | |a Cañete, Juan D. |e verfasserin |4 aut | |
| 700 | 1 | |a Blanco, Francisco J. |e verfasserin |4 aut | |
| 700 | 1 | |a Ruano, Yolanda |e verfasserin |4 aut | |
| 700 | 1 | |a Criado, Gabriel |e verfasserin |4 aut | |
| 700 | 1 | |a Pablos, José L. |e verfasserin |4 aut | |
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10.1186/s12860-020-00317-7 doi (DE-627)SPR041708989 (SPR)s12860-020-00317-7-e DE-627 ger DE-627 rakwb eng 570 ASE 570 610 ASE 42.15 bkl Valin, Alvaro verfasserin aut IL6/sIL6R regulates TNFα-inflammatory response in synovial fibroblasts through modulation of transcriptional and post-transcriptional mechanisms 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Introduction The clinical efficacy of specific interleukin-6 inhibitors has confirmed the central role of IL6 in rheumatoid arthritis (RA). However the local role of IL6, in particular in synovial fibroblasts (SF) as a direct cellular target to IL6/sIL6R signal is not well characterized. The purpose of the study was to characterize the crosstalk between TNFα and IL6/sIL6R signaling to the effector pro-inflammatory response of SF. Methods SF lines were stimulated with either TNFα, IL6/sIL6R, or both together, for the time and dose indicated for each experiment, and where indicated, cells were treated with inhibitors actinomycin D, adalimumab, ruxolitinib and cycloheximide. mRNA expression of cytokines, chemokines and matrix metalloproteases (MMPs) were analyzed by quantitative RT-PCR. Level of IL8/CXCL8 and CCL8 in culture supernatants was measured by ELISA. Mononuclear and polymorphonuclear cells migration assays were assessed by transwell using conditioned medium from SF cultures. Statistical analyses were performed as indicated in the corresponding figure legends and a p-value < 0.05 was considered statistically significant. Results The stimulation of SF with IL6/sIL6R and TNFα, cooperatively promotes the expression of mono- and lymphocytic chemokines such as IL6, CCL8 and CCL2, as well as matrix degrading enzymes such as MMP1, while inhibiting the induction of central neutrophil chemokines such as IL8/CXCL8. These changes in the pattern of chemokines expression resulted in reduced polymorphonuclear (PMN) and increased mononuclear cells (MNC) chemoattraction by SF. Mechanistic analyses of the temporal expression of genes demonstrated that the cooperative regulation mediated by these two factors is mostly induced through de novo transcriptional mechanisms activated by IL6/sIL6R. Furthermore, we also demonstrate that TNFα and IL6/sIL6R cooperation is partially mediated by the expression of secondary factors signaling through JAK/STAT pathways. Conclusions These results point out to a highly orchestrated response to IL6 in TNFα-induced SF and provide additional insights into the role of IL6/sIL6R in the context of RA, highlighting the contribution of IL6/sIL6R to the interplay of SF with other inflammatory cells. IL6 (dpeaa)DE-He213 TNFα (dpeaa)DE-He213 Soluble receptor (dpeaa)DE-He213 Synovial fibroblast (dpeaa)DE-He213 Inflammatory response (dpeaa)DE-He213 Rheumatoid arthritis (dpeaa)DE-He213 Cross-talk (dpeaa)DE-He213 Transcriptional mechanisms (dpeaa)DE-He213 Post-transcriptional mechanisms (dpeaa)DE-He213 JAK/STAT (dpeaa)DE-He213 Del Rey, Manuel J. verfasserin aut Municio, Cristina verfasserin aut Usategui, Alicia verfasserin aut Romero, Marina verfasserin aut Fernández-Felipe, Jesús verfasserin aut Cañete, Juan D. verfasserin aut Blanco, Francisco J. verfasserin aut Ruano, Yolanda verfasserin aut Criado, Gabriel verfasserin aut Pablos, José L. verfasserin aut Enthalten in BMC cell biology London : BioMed Central, 2000 21(2020), 1 vom: 30. Okt. (DE-627)326644830 (DE-600)2041486-9 1471-2121 nnns volume:21 year:2020 number:1 day:30 month:10 https://dx.doi.org/10.1186/s12860-020-00317-7 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_22 GBV_ILN_2003 GBV_ILN_2008 GBV_ILN_2021 GBV_ILN_4305 42.15 ASE AR 21 2020 1 30 10 |
| spelling |
10.1186/s12860-020-00317-7 doi (DE-627)SPR041708989 (SPR)s12860-020-00317-7-e DE-627 ger DE-627 rakwb eng 570 ASE 570 610 ASE 42.15 bkl Valin, Alvaro verfasserin aut IL6/sIL6R regulates TNFα-inflammatory response in synovial fibroblasts through modulation of transcriptional and post-transcriptional mechanisms 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Introduction The clinical efficacy of specific interleukin-6 inhibitors has confirmed the central role of IL6 in rheumatoid arthritis (RA). However the local role of IL6, in particular in synovial fibroblasts (SF) as a direct cellular target to IL6/sIL6R signal is not well characterized. The purpose of the study was to characterize the crosstalk between TNFα and IL6/sIL6R signaling to the effector pro-inflammatory response of SF. Methods SF lines were stimulated with either TNFα, IL6/sIL6R, or both together, for the time and dose indicated for each experiment, and where indicated, cells were treated with inhibitors actinomycin D, adalimumab, ruxolitinib and cycloheximide. mRNA expression of cytokines, chemokines and matrix metalloproteases (MMPs) were analyzed by quantitative RT-PCR. Level of IL8/CXCL8 and CCL8 in culture supernatants was measured by ELISA. Mononuclear and polymorphonuclear cells migration assays were assessed by transwell using conditioned medium from SF cultures. Statistical analyses were performed as indicated in the corresponding figure legends and a p-value < 0.05 was considered statistically significant. Results The stimulation of SF with IL6/sIL6R and TNFα, cooperatively promotes the expression of mono- and lymphocytic chemokines such as IL6, CCL8 and CCL2, as well as matrix degrading enzymes such as MMP1, while inhibiting the induction of central neutrophil chemokines such as IL8/CXCL8. These changes in the pattern of chemokines expression resulted in reduced polymorphonuclear (PMN) and increased mononuclear cells (MNC) chemoattraction by SF. Mechanistic analyses of the temporal expression of genes demonstrated that the cooperative regulation mediated by these two factors is mostly induced through de novo transcriptional mechanisms activated by IL6/sIL6R. Furthermore, we also demonstrate that TNFα and IL6/sIL6R cooperation is partially mediated by the expression of secondary factors signaling through JAK/STAT pathways. Conclusions These results point out to a highly orchestrated response to IL6 in TNFα-induced SF and provide additional insights into the role of IL6/sIL6R in the context of RA, highlighting the contribution of IL6/sIL6R to the interplay of SF with other inflammatory cells. IL6 (dpeaa)DE-He213 TNFα (dpeaa)DE-He213 Soluble receptor (dpeaa)DE-He213 Synovial fibroblast (dpeaa)DE-He213 Inflammatory response (dpeaa)DE-He213 Rheumatoid arthritis (dpeaa)DE-He213 Cross-talk (dpeaa)DE-He213 Transcriptional mechanisms (dpeaa)DE-He213 Post-transcriptional mechanisms (dpeaa)DE-He213 JAK/STAT (dpeaa)DE-He213 Del Rey, Manuel J. verfasserin aut Municio, Cristina verfasserin aut Usategui, Alicia verfasserin aut Romero, Marina verfasserin aut Fernández-Felipe, Jesús verfasserin aut Cañete, Juan D. verfasserin aut Blanco, Francisco J. verfasserin aut Ruano, Yolanda verfasserin aut Criado, Gabriel verfasserin aut Pablos, José L. verfasserin aut Enthalten in BMC cell biology London : BioMed Central, 2000 21(2020), 1 vom: 30. Okt. (DE-627)326644830 (DE-600)2041486-9 1471-2121 nnns volume:21 year:2020 number:1 day:30 month:10 https://dx.doi.org/10.1186/s12860-020-00317-7 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_22 GBV_ILN_2003 GBV_ILN_2008 GBV_ILN_2021 GBV_ILN_4305 42.15 ASE AR 21 2020 1 30 10 |
| allfields_unstemmed |
10.1186/s12860-020-00317-7 doi (DE-627)SPR041708989 (SPR)s12860-020-00317-7-e DE-627 ger DE-627 rakwb eng 570 ASE 570 610 ASE 42.15 bkl Valin, Alvaro verfasserin aut IL6/sIL6R regulates TNFα-inflammatory response in synovial fibroblasts through modulation of transcriptional and post-transcriptional mechanisms 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Introduction The clinical efficacy of specific interleukin-6 inhibitors has confirmed the central role of IL6 in rheumatoid arthritis (RA). However the local role of IL6, in particular in synovial fibroblasts (SF) as a direct cellular target to IL6/sIL6R signal is not well characterized. The purpose of the study was to characterize the crosstalk between TNFα and IL6/sIL6R signaling to the effector pro-inflammatory response of SF. Methods SF lines were stimulated with either TNFα, IL6/sIL6R, or both together, for the time and dose indicated for each experiment, and where indicated, cells were treated with inhibitors actinomycin D, adalimumab, ruxolitinib and cycloheximide. mRNA expression of cytokines, chemokines and matrix metalloproteases (MMPs) were analyzed by quantitative RT-PCR. Level of IL8/CXCL8 and CCL8 in culture supernatants was measured by ELISA. Mononuclear and polymorphonuclear cells migration assays were assessed by transwell using conditioned medium from SF cultures. Statistical analyses were performed as indicated in the corresponding figure legends and a p-value < 0.05 was considered statistically significant. Results The stimulation of SF with IL6/sIL6R and TNFα, cooperatively promotes the expression of mono- and lymphocytic chemokines such as IL6, CCL8 and CCL2, as well as matrix degrading enzymes such as MMP1, while inhibiting the induction of central neutrophil chemokines such as IL8/CXCL8. These changes in the pattern of chemokines expression resulted in reduced polymorphonuclear (PMN) and increased mononuclear cells (MNC) chemoattraction by SF. Mechanistic analyses of the temporal expression of genes demonstrated that the cooperative regulation mediated by these two factors is mostly induced through de novo transcriptional mechanisms activated by IL6/sIL6R. Furthermore, we also demonstrate that TNFα and IL6/sIL6R cooperation is partially mediated by the expression of secondary factors signaling through JAK/STAT pathways. Conclusions These results point out to a highly orchestrated response to IL6 in TNFα-induced SF and provide additional insights into the role of IL6/sIL6R in the context of RA, highlighting the contribution of IL6/sIL6R to the interplay of SF with other inflammatory cells. IL6 (dpeaa)DE-He213 TNFα (dpeaa)DE-He213 Soluble receptor (dpeaa)DE-He213 Synovial fibroblast (dpeaa)DE-He213 Inflammatory response (dpeaa)DE-He213 Rheumatoid arthritis (dpeaa)DE-He213 Cross-talk (dpeaa)DE-He213 Transcriptional mechanisms (dpeaa)DE-He213 Post-transcriptional mechanisms (dpeaa)DE-He213 JAK/STAT (dpeaa)DE-He213 Del Rey, Manuel J. verfasserin aut Municio, Cristina verfasserin aut Usategui, Alicia verfasserin aut Romero, Marina verfasserin aut Fernández-Felipe, Jesús verfasserin aut Cañete, Juan D. verfasserin aut Blanco, Francisco J. verfasserin aut Ruano, Yolanda verfasserin aut Criado, Gabriel verfasserin aut Pablos, José L. verfasserin aut Enthalten in BMC cell biology London : BioMed Central, 2000 21(2020), 1 vom: 30. Okt. (DE-627)326644830 (DE-600)2041486-9 1471-2121 nnns volume:21 year:2020 number:1 day:30 month:10 https://dx.doi.org/10.1186/s12860-020-00317-7 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_22 GBV_ILN_2003 GBV_ILN_2008 GBV_ILN_2021 GBV_ILN_4305 42.15 ASE AR 21 2020 1 30 10 |
| allfieldsGer |
10.1186/s12860-020-00317-7 doi (DE-627)SPR041708989 (SPR)s12860-020-00317-7-e DE-627 ger DE-627 rakwb eng 570 ASE 570 610 ASE 42.15 bkl Valin, Alvaro verfasserin aut IL6/sIL6R regulates TNFα-inflammatory response in synovial fibroblasts through modulation of transcriptional and post-transcriptional mechanisms 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Introduction The clinical efficacy of specific interleukin-6 inhibitors has confirmed the central role of IL6 in rheumatoid arthritis (RA). However the local role of IL6, in particular in synovial fibroblasts (SF) as a direct cellular target to IL6/sIL6R signal is not well characterized. The purpose of the study was to characterize the crosstalk between TNFα and IL6/sIL6R signaling to the effector pro-inflammatory response of SF. Methods SF lines were stimulated with either TNFα, IL6/sIL6R, or both together, for the time and dose indicated for each experiment, and where indicated, cells were treated with inhibitors actinomycin D, adalimumab, ruxolitinib and cycloheximide. mRNA expression of cytokines, chemokines and matrix metalloproteases (MMPs) were analyzed by quantitative RT-PCR. Level of IL8/CXCL8 and CCL8 in culture supernatants was measured by ELISA. Mononuclear and polymorphonuclear cells migration assays were assessed by transwell using conditioned medium from SF cultures. Statistical analyses were performed as indicated in the corresponding figure legends and a p-value < 0.05 was considered statistically significant. Results The stimulation of SF with IL6/sIL6R and TNFα, cooperatively promotes the expression of mono- and lymphocytic chemokines such as IL6, CCL8 and CCL2, as well as matrix degrading enzymes such as MMP1, while inhibiting the induction of central neutrophil chemokines such as IL8/CXCL8. These changes in the pattern of chemokines expression resulted in reduced polymorphonuclear (PMN) and increased mononuclear cells (MNC) chemoattraction by SF. Mechanistic analyses of the temporal expression of genes demonstrated that the cooperative regulation mediated by these two factors is mostly induced through de novo transcriptional mechanisms activated by IL6/sIL6R. Furthermore, we also demonstrate that TNFα and IL6/sIL6R cooperation is partially mediated by the expression of secondary factors signaling through JAK/STAT pathways. Conclusions These results point out to a highly orchestrated response to IL6 in TNFα-induced SF and provide additional insights into the role of IL6/sIL6R in the context of RA, highlighting the contribution of IL6/sIL6R to the interplay of SF with other inflammatory cells. IL6 (dpeaa)DE-He213 TNFα (dpeaa)DE-He213 Soluble receptor (dpeaa)DE-He213 Synovial fibroblast (dpeaa)DE-He213 Inflammatory response (dpeaa)DE-He213 Rheumatoid arthritis (dpeaa)DE-He213 Cross-talk (dpeaa)DE-He213 Transcriptional mechanisms (dpeaa)DE-He213 Post-transcriptional mechanisms (dpeaa)DE-He213 JAK/STAT (dpeaa)DE-He213 Del Rey, Manuel J. verfasserin aut Municio, Cristina verfasserin aut Usategui, Alicia verfasserin aut Romero, Marina verfasserin aut Fernández-Felipe, Jesús verfasserin aut Cañete, Juan D. verfasserin aut Blanco, Francisco J. verfasserin aut Ruano, Yolanda verfasserin aut Criado, Gabriel verfasserin aut Pablos, José L. verfasserin aut Enthalten in BMC cell biology London : BioMed Central, 2000 21(2020), 1 vom: 30. Okt. (DE-627)326644830 (DE-600)2041486-9 1471-2121 nnns volume:21 year:2020 number:1 day:30 month:10 https://dx.doi.org/10.1186/s12860-020-00317-7 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_22 GBV_ILN_2003 GBV_ILN_2008 GBV_ILN_2021 GBV_ILN_4305 42.15 ASE AR 21 2020 1 30 10 |
| allfieldsSound |
10.1186/s12860-020-00317-7 doi (DE-627)SPR041708989 (SPR)s12860-020-00317-7-e DE-627 ger DE-627 rakwb eng 570 ASE 570 610 ASE 42.15 bkl Valin, Alvaro verfasserin aut IL6/sIL6R regulates TNFα-inflammatory response in synovial fibroblasts through modulation of transcriptional and post-transcriptional mechanisms 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Introduction The clinical efficacy of specific interleukin-6 inhibitors has confirmed the central role of IL6 in rheumatoid arthritis (RA). However the local role of IL6, in particular in synovial fibroblasts (SF) as a direct cellular target to IL6/sIL6R signal is not well characterized. The purpose of the study was to characterize the crosstalk between TNFα and IL6/sIL6R signaling to the effector pro-inflammatory response of SF. Methods SF lines were stimulated with either TNFα, IL6/sIL6R, or both together, for the time and dose indicated for each experiment, and where indicated, cells were treated with inhibitors actinomycin D, adalimumab, ruxolitinib and cycloheximide. mRNA expression of cytokines, chemokines and matrix metalloproteases (MMPs) were analyzed by quantitative RT-PCR. Level of IL8/CXCL8 and CCL8 in culture supernatants was measured by ELISA. Mononuclear and polymorphonuclear cells migration assays were assessed by transwell using conditioned medium from SF cultures. Statistical analyses were performed as indicated in the corresponding figure legends and a p-value < 0.05 was considered statistically significant. Results The stimulation of SF with IL6/sIL6R and TNFα, cooperatively promotes the expression of mono- and lymphocytic chemokines such as IL6, CCL8 and CCL2, as well as matrix degrading enzymes such as MMP1, while inhibiting the induction of central neutrophil chemokines such as IL8/CXCL8. These changes in the pattern of chemokines expression resulted in reduced polymorphonuclear (PMN) and increased mononuclear cells (MNC) chemoattraction by SF. Mechanistic analyses of the temporal expression of genes demonstrated that the cooperative regulation mediated by these two factors is mostly induced through de novo transcriptional mechanisms activated by IL6/sIL6R. Furthermore, we also demonstrate that TNFα and IL6/sIL6R cooperation is partially mediated by the expression of secondary factors signaling through JAK/STAT pathways. Conclusions These results point out to a highly orchestrated response to IL6 in TNFα-induced SF and provide additional insights into the role of IL6/sIL6R in the context of RA, highlighting the contribution of IL6/sIL6R to the interplay of SF with other inflammatory cells. IL6 (dpeaa)DE-He213 TNFα (dpeaa)DE-He213 Soluble receptor (dpeaa)DE-He213 Synovial fibroblast (dpeaa)DE-He213 Inflammatory response (dpeaa)DE-He213 Rheumatoid arthritis (dpeaa)DE-He213 Cross-talk (dpeaa)DE-He213 Transcriptional mechanisms (dpeaa)DE-He213 Post-transcriptional mechanisms (dpeaa)DE-He213 JAK/STAT (dpeaa)DE-He213 Del Rey, Manuel J. verfasserin aut Municio, Cristina verfasserin aut Usategui, Alicia verfasserin aut Romero, Marina verfasserin aut Fernández-Felipe, Jesús verfasserin aut Cañete, Juan D. verfasserin aut Blanco, Francisco J. verfasserin aut Ruano, Yolanda verfasserin aut Criado, Gabriel verfasserin aut Pablos, José L. verfasserin aut Enthalten in BMC cell biology London : BioMed Central, 2000 21(2020), 1 vom: 30. Okt. (DE-627)326644830 (DE-600)2041486-9 1471-2121 nnns volume:21 year:2020 number:1 day:30 month:10 https://dx.doi.org/10.1186/s12860-020-00317-7 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_22 GBV_ILN_2003 GBV_ILN_2008 GBV_ILN_2021 GBV_ILN_4305 42.15 ASE AR 21 2020 1 30 10 |
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However the local role of IL6, in particular in synovial fibroblasts (SF) as a direct cellular target to IL6/sIL6R signal is not well characterized. The purpose of the study was to characterize the crosstalk between TNFα and IL6/sIL6R signaling to the effector pro-inflammatory response of SF. Methods SF lines were stimulated with either TNFα, IL6/sIL6R, or both together, for the time and dose indicated for each experiment, and where indicated, cells were treated with inhibitors actinomycin D, adalimumab, ruxolitinib and cycloheximide. mRNA expression of cytokines, chemokines and matrix metalloproteases (MMPs) were analyzed by quantitative RT-PCR. Level of IL8/CXCL8 and CCL8 in culture supernatants was measured by ELISA. Mononuclear and polymorphonuclear cells migration assays were assessed by transwell using conditioned medium from SF cultures. Statistical analyses were performed as indicated in the corresponding figure legends and a p-value < 0.05 was considered statistically significant. Results The stimulation of SF with IL6/sIL6R and TNFα, cooperatively promotes the expression of mono- and lymphocytic chemokines such as IL6, CCL8 and CCL2, as well as matrix degrading enzymes such as MMP1, while inhibiting the induction of central neutrophil chemokines such as IL8/CXCL8. These changes in the pattern of chemokines expression resulted in reduced polymorphonuclear (PMN) and increased mononuclear cells (MNC) chemoattraction by SF. Mechanistic analyses of the temporal expression of genes demonstrated that the cooperative regulation mediated by these two factors is mostly induced through de novo transcriptional mechanisms activated by IL6/sIL6R. Furthermore, we also demonstrate that TNFα and IL6/sIL6R cooperation is partially mediated by the expression of secondary factors signaling through JAK/STAT pathways. 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Valin, Alvaro |
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Valin, Alvaro ddc 570 bkl 42.15 misc IL6 misc TNFα misc Soluble receptor misc Synovial fibroblast misc Inflammatory response misc Rheumatoid arthritis misc Cross-talk misc Transcriptional mechanisms misc Post-transcriptional mechanisms misc JAK/STAT IL6/sIL6R regulates TNFα-inflammatory response in synovial fibroblasts through modulation of transcriptional and post-transcriptional mechanisms |
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570 ASE 570 610 ASE 42.15 bkl IL6/sIL6R regulates TNFα-inflammatory response in synovial fibroblasts through modulation of transcriptional and post-transcriptional mechanisms IL6 (dpeaa)DE-He213 TNFα (dpeaa)DE-He213 Soluble receptor (dpeaa)DE-He213 Synovial fibroblast (dpeaa)DE-He213 Inflammatory response (dpeaa)DE-He213 Rheumatoid arthritis (dpeaa)DE-He213 Cross-talk (dpeaa)DE-He213 Transcriptional mechanisms (dpeaa)DE-He213 Post-transcriptional mechanisms (dpeaa)DE-He213 JAK/STAT (dpeaa)DE-He213 |
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IL6/sIL6R regulates TNFα-inflammatory response in synovial fibroblasts through modulation of transcriptional and post-transcriptional mechanisms |
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IL6/sIL6R regulates TNFα-inflammatory response in synovial fibroblasts through modulation of transcriptional and post-transcriptional mechanisms |
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Valin, Alvaro Del Rey, Manuel J. Municio, Cristina Usategui, Alicia Romero, Marina Fernández-Felipe, Jesús Cañete, Juan D. Blanco, Francisco J. Ruano, Yolanda Criado, Gabriel Pablos, José L. |
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il6/sil6r regulates tnfα-inflammatory response in synovial fibroblasts through modulation of transcriptional and post-transcriptional mechanisms |
| title_auth |
IL6/sIL6R regulates TNFα-inflammatory response in synovial fibroblasts through modulation of transcriptional and post-transcriptional mechanisms |
| abstract |
Introduction The clinical efficacy of specific interleukin-6 inhibitors has confirmed the central role of IL6 in rheumatoid arthritis (RA). However the local role of IL6, in particular in synovial fibroblasts (SF) as a direct cellular target to IL6/sIL6R signal is not well characterized. The purpose of the study was to characterize the crosstalk between TNFα and IL6/sIL6R signaling to the effector pro-inflammatory response of SF. Methods SF lines were stimulated with either TNFα, IL6/sIL6R, or both together, for the time and dose indicated for each experiment, and where indicated, cells were treated with inhibitors actinomycin D, adalimumab, ruxolitinib and cycloheximide. mRNA expression of cytokines, chemokines and matrix metalloproteases (MMPs) were analyzed by quantitative RT-PCR. Level of IL8/CXCL8 and CCL8 in culture supernatants was measured by ELISA. Mononuclear and polymorphonuclear cells migration assays were assessed by transwell using conditioned medium from SF cultures. Statistical analyses were performed as indicated in the corresponding figure legends and a p-value < 0.05 was considered statistically significant. Results The stimulation of SF with IL6/sIL6R and TNFα, cooperatively promotes the expression of mono- and lymphocytic chemokines such as IL6, CCL8 and CCL2, as well as matrix degrading enzymes such as MMP1, while inhibiting the induction of central neutrophil chemokines such as IL8/CXCL8. These changes in the pattern of chemokines expression resulted in reduced polymorphonuclear (PMN) and increased mononuclear cells (MNC) chemoattraction by SF. Mechanistic analyses of the temporal expression of genes demonstrated that the cooperative regulation mediated by these two factors is mostly induced through de novo transcriptional mechanisms activated by IL6/sIL6R. Furthermore, we also demonstrate that TNFα and IL6/sIL6R cooperation is partially mediated by the expression of secondary factors signaling through JAK/STAT pathways. Conclusions These results point out to a highly orchestrated response to IL6 in TNFα-induced SF and provide additional insights into the role of IL6/sIL6R in the context of RA, highlighting the contribution of IL6/sIL6R to the interplay of SF with other inflammatory cells. |
| abstractGer |
Introduction The clinical efficacy of specific interleukin-6 inhibitors has confirmed the central role of IL6 in rheumatoid arthritis (RA). However the local role of IL6, in particular in synovial fibroblasts (SF) as a direct cellular target to IL6/sIL6R signal is not well characterized. The purpose of the study was to characterize the crosstalk between TNFα and IL6/sIL6R signaling to the effector pro-inflammatory response of SF. Methods SF lines were stimulated with either TNFα, IL6/sIL6R, or both together, for the time and dose indicated for each experiment, and where indicated, cells were treated with inhibitors actinomycin D, adalimumab, ruxolitinib and cycloheximide. mRNA expression of cytokines, chemokines and matrix metalloproteases (MMPs) were analyzed by quantitative RT-PCR. Level of IL8/CXCL8 and CCL8 in culture supernatants was measured by ELISA. Mononuclear and polymorphonuclear cells migration assays were assessed by transwell using conditioned medium from SF cultures. Statistical analyses were performed as indicated in the corresponding figure legends and a p-value < 0.05 was considered statistically significant. Results The stimulation of SF with IL6/sIL6R and TNFα, cooperatively promotes the expression of mono- and lymphocytic chemokines such as IL6, CCL8 and CCL2, as well as matrix degrading enzymes such as MMP1, while inhibiting the induction of central neutrophil chemokines such as IL8/CXCL8. These changes in the pattern of chemokines expression resulted in reduced polymorphonuclear (PMN) and increased mononuclear cells (MNC) chemoattraction by SF. Mechanistic analyses of the temporal expression of genes demonstrated that the cooperative regulation mediated by these two factors is mostly induced through de novo transcriptional mechanisms activated by IL6/sIL6R. Furthermore, we also demonstrate that TNFα and IL6/sIL6R cooperation is partially mediated by the expression of secondary factors signaling through JAK/STAT pathways. Conclusions These results point out to a highly orchestrated response to IL6 in TNFα-induced SF and provide additional insights into the role of IL6/sIL6R in the context of RA, highlighting the contribution of IL6/sIL6R to the interplay of SF with other inflammatory cells. |
| abstract_unstemmed |
Introduction The clinical efficacy of specific interleukin-6 inhibitors has confirmed the central role of IL6 in rheumatoid arthritis (RA). However the local role of IL6, in particular in synovial fibroblasts (SF) as a direct cellular target to IL6/sIL6R signal is not well characterized. The purpose of the study was to characterize the crosstalk between TNFα and IL6/sIL6R signaling to the effector pro-inflammatory response of SF. Methods SF lines were stimulated with either TNFα, IL6/sIL6R, or both together, for the time and dose indicated for each experiment, and where indicated, cells were treated with inhibitors actinomycin D, adalimumab, ruxolitinib and cycloheximide. mRNA expression of cytokines, chemokines and matrix metalloproteases (MMPs) were analyzed by quantitative RT-PCR. Level of IL8/CXCL8 and CCL8 in culture supernatants was measured by ELISA. Mononuclear and polymorphonuclear cells migration assays were assessed by transwell using conditioned medium from SF cultures. Statistical analyses were performed as indicated in the corresponding figure legends and a p-value < 0.05 was considered statistically significant. Results The stimulation of SF with IL6/sIL6R and TNFα, cooperatively promotes the expression of mono- and lymphocytic chemokines such as IL6, CCL8 and CCL2, as well as matrix degrading enzymes such as MMP1, while inhibiting the induction of central neutrophil chemokines such as IL8/CXCL8. These changes in the pattern of chemokines expression resulted in reduced polymorphonuclear (PMN) and increased mononuclear cells (MNC) chemoattraction by SF. Mechanistic analyses of the temporal expression of genes demonstrated that the cooperative regulation mediated by these two factors is mostly induced through de novo transcriptional mechanisms activated by IL6/sIL6R. Furthermore, we also demonstrate that TNFα and IL6/sIL6R cooperation is partially mediated by the expression of secondary factors signaling through JAK/STAT pathways. Conclusions These results point out to a highly orchestrated response to IL6 in TNFα-induced SF and provide additional insights into the role of IL6/sIL6R in the context of RA, highlighting the contribution of IL6/sIL6R to the interplay of SF with other inflammatory cells. |
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IL6/sIL6R regulates TNFα-inflammatory response in synovial fibroblasts through modulation of transcriptional and post-transcriptional mechanisms |
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However the local role of IL6, in particular in synovial fibroblasts (SF) as a direct cellular target to IL6/sIL6R signal is not well characterized. The purpose of the study was to characterize the crosstalk between TNFα and IL6/sIL6R signaling to the effector pro-inflammatory response of SF. Methods SF lines were stimulated with either TNFα, IL6/sIL6R, or both together, for the time and dose indicated for each experiment, and where indicated, cells were treated with inhibitors actinomycin D, adalimumab, ruxolitinib and cycloheximide. mRNA expression of cytokines, chemokines and matrix metalloproteases (MMPs) were analyzed by quantitative RT-PCR. Level of IL8/CXCL8 and CCL8 in culture supernatants was measured by ELISA. Mononuclear and polymorphonuclear cells migration assays were assessed by transwell using conditioned medium from SF cultures. Statistical analyses were performed as indicated in the corresponding figure legends and a p-value < 0.05 was considered statistically significant. Results The stimulation of SF with IL6/sIL6R and TNFα, cooperatively promotes the expression of mono- and lymphocytic chemokines such as IL6, CCL8 and CCL2, as well as matrix degrading enzymes such as MMP1, while inhibiting the induction of central neutrophil chemokines such as IL8/CXCL8. These changes in the pattern of chemokines expression resulted in reduced polymorphonuclear (PMN) and increased mononuclear cells (MNC) chemoattraction by SF. Mechanistic analyses of the temporal expression of genes demonstrated that the cooperative regulation mediated by these two factors is mostly induced through de novo transcriptional mechanisms activated by IL6/sIL6R. Furthermore, we also demonstrate that TNFα and IL6/sIL6R cooperation is partially mediated by the expression of secondary factors signaling through JAK/STAT pathways. Conclusions These results point out to a highly orchestrated response to IL6 in TNFα-induced SF and provide additional insights into the role of IL6/sIL6R in the context of RA, highlighting the contribution of IL6/sIL6R to the interplay of SF with other inflammatory cells.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">IL6</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">TNFα</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Soluble receptor</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Synovial fibroblast</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Inflammatory response</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Rheumatoid arthritis</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Cross-talk</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Transcriptional mechanisms</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Post-transcriptional mechanisms</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">JAK/STAT</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Del Rey, Manuel J.</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Municio, Cristina</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Usategui, Alicia</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Romero, Marina</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Fernández-Felipe, Jesús</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Cañete, Juan D.</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Blanco, Francisco J.</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Ruano, Yolanda</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Criado, Gabriel</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Pablos, José L.</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">BMC cell biology</subfield><subfield code="d">London : BioMed Central, 2000</subfield><subfield code="g">21(2020), 1 vom: 30. 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