Tocilizumab Contributes to the Inflammatory Status of Mature Dendritic Cells through Interleukin-6 Receptor Subunits Modulation
Tocilizumab, a humanized anti-IL-6 receptor α (IL-6Rα) is widely used in the treatment of a panel of pathologies such as adult and juvenile rheumatoid arthritis (RA) and the systemic form of juvenile idiopathic arthritis in children. Its indications are expected to be largely extended to other infla...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2017-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2017.00926/full |
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| author | Daniel Meley Audrey Héraud Valerie Gouilleux-Gruart Valerie Gouilleux-Gruart Fabrice Ivanes Fabrice Ivanes Florence Velge-Roussel Florence Velge-Roussel |
| author_facet | Daniel Meley Audrey Héraud Valerie Gouilleux-Gruart Valerie Gouilleux-Gruart Fabrice Ivanes Fabrice Ivanes Florence Velge-Roussel Florence Velge-Roussel |
| author_sort | Daniel Meley |
| collection | DOAJ |
| description | Tocilizumab, a humanized anti-IL-6 receptor α (IL-6Rα) is widely used in the treatment of a panel of pathologies such as adult and juvenile rheumatoid arthritis (RA) and the systemic form of juvenile idiopathic arthritis in children. Its indications are expected to be largely extended to other inflammatory diseases in close future. Dendritic cells (DCs) appear to be deeply involved in the immunopathology of these diseases, yet the effects of tocilizumab on these cells were poorly studied. In this study, we explored the effect of tocilizumab on the regulation of IL-6R subunits [gp130, soluble form of IL-6Rα (sIL-6Rα), and mIL-6Rα] in human monocyte-derived DCs. Human DCs were derived from CD14+ monocytes purified with beads with IL-4 and granulocyte macrophage colony-stimulating factor. Ex vivo cultures of DCs were performed in the presence of tocilizumab. Using lipopolysaccharide (LPS) maturation of DCs, we demonstrated that tocilizumab did not inhibit IL-6 secretion, enhanced mIL-6Rα expression, and largely increased sIL-6Rα secretion. MAPK modulated STAT3 phosphorylation and surface expression of IL-6Rα in LPS-DCs. Tocilizumab had no impact on STAT3 phosphorylation in LPS-DCs while both LPS and IL-6 increased its activation. Tocilizumab modulated the regulation of IL-6R subunits leading to an inflammatory status of DCs and a massive secretion of IL-6Rα. Our results demonstrate that DCs acquire a pro-inflammatory profile following tocilizumab treatment, becoming a major source of IL-6 trans-signaling activation that might explain the poor clinical benefit in some RA patients. |
| first_indexed | 2024-12-23T10:50:39Z |
| format | Article |
| id | doaj.art-e9b318461c874e768bc78fbf7321d6fe |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-23T10:50:39Z |
| publishDate | 2017-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-e9b318461c874e768bc78fbf7321d6fe2022-12-21T17:49:54ZengFrontiers Media S.A.Frontiers in Immunology1664-32242017-08-01810.3389/fimmu.2017.00926255267Tocilizumab Contributes to the Inflammatory Status of Mature Dendritic Cells through Interleukin-6 Receptor Subunits ModulationDaniel Meley0Audrey Héraud1Valerie Gouilleux-Gruart2Valerie Gouilleux-Gruart3Fabrice Ivanes4Fabrice Ivanes5Florence Velge-Roussel6Florence Velge-Roussel7EA 4245 Cellules Dendritiques, Immuno-modulation et Greffes, Université François-Rabelais de Tours, UFR de Médecine, Tours, FranceEA 4245 Cellules Dendritiques, Immuno-modulation et Greffes, Université François-Rabelais de Tours, UFR de Médecine, Tours, FranceCNRS UMR 7292; Université François-Rabelais de Tours, UFR de Médecine, Tours, FranceDepartment of Immunology, CHRU de Tours, Tours, FranceEA 4245 Cellules Dendritiques, Immuno-modulation et Greffes, Université François-Rabelais de Tours, UFR de Médecine, Tours, FranceService de Cardiologie, CHRU de Tours, Tours, FranceEA 4245 Cellules Dendritiques, Immuno-modulation et Greffes, Université François-Rabelais de Tours, UFR de Médecine, Tours, FranceUFR des Sciences Pharmaceutiques, Tours, FranceTocilizumab, a humanized anti-IL-6 receptor α (IL-6Rα) is widely used in the treatment of a panel of pathologies such as adult and juvenile rheumatoid arthritis (RA) and the systemic form of juvenile idiopathic arthritis in children. Its indications are expected to be largely extended to other inflammatory diseases in close future. Dendritic cells (DCs) appear to be deeply involved in the immunopathology of these diseases, yet the effects of tocilizumab on these cells were poorly studied. In this study, we explored the effect of tocilizumab on the regulation of IL-6R subunits [gp130, soluble form of IL-6Rα (sIL-6Rα), and mIL-6Rα] in human monocyte-derived DCs. Human DCs were derived from CD14+ monocytes purified with beads with IL-4 and granulocyte macrophage colony-stimulating factor. Ex vivo cultures of DCs were performed in the presence of tocilizumab. Using lipopolysaccharide (LPS) maturation of DCs, we demonstrated that tocilizumab did not inhibit IL-6 secretion, enhanced mIL-6Rα expression, and largely increased sIL-6Rα secretion. MAPK modulated STAT3 phosphorylation and surface expression of IL-6Rα in LPS-DCs. Tocilizumab had no impact on STAT3 phosphorylation in LPS-DCs while both LPS and IL-6 increased its activation. Tocilizumab modulated the regulation of IL-6R subunits leading to an inflammatory status of DCs and a massive secretion of IL-6Rα. Our results demonstrate that DCs acquire a pro-inflammatory profile following tocilizumab treatment, becoming a major source of IL-6 trans-signaling activation that might explain the poor clinical benefit in some RA patients.http://journal.frontiersin.org/article/10.3389/fimmu.2017.00926/fulldendritic celltocilizumabIL-6 receptor subunitsrheumatoid arthritisinflammation |
| spellingShingle | Daniel Meley Audrey Héraud Valerie Gouilleux-Gruart Valerie Gouilleux-Gruart Fabrice Ivanes Fabrice Ivanes Florence Velge-Roussel Florence Velge-Roussel Tocilizumab Contributes to the Inflammatory Status of Mature Dendritic Cells through Interleukin-6 Receptor Subunits Modulation Frontiers in Immunology dendritic cell tocilizumab IL-6 receptor subunits rheumatoid arthritis inflammation |
| title | Tocilizumab Contributes to the Inflammatory Status of Mature Dendritic Cells through Interleukin-6 Receptor Subunits Modulation |
| title_full | Tocilizumab Contributes to the Inflammatory Status of Mature Dendritic Cells through Interleukin-6 Receptor Subunits Modulation |
| title_fullStr | Tocilizumab Contributes to the Inflammatory Status of Mature Dendritic Cells through Interleukin-6 Receptor Subunits Modulation |
| title_full_unstemmed | Tocilizumab Contributes to the Inflammatory Status of Mature Dendritic Cells through Interleukin-6 Receptor Subunits Modulation |
| title_short | Tocilizumab Contributes to the Inflammatory Status of Mature Dendritic Cells through Interleukin-6 Receptor Subunits Modulation |
| title_sort | tocilizumab contributes to the inflammatory status of mature dendritic cells through interleukin 6 receptor subunits modulation |
| topic | dendritic cell tocilizumab IL-6 receptor subunits rheumatoid arthritis inflammation |
| url | http://journal.frontiersin.org/article/10.3389/fimmu.2017.00926/full |
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