PMID- 28861079
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20191120
IS  - 1664-3224 (Print)
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 8
DP  - 2017
TI  - Tocilizumab Contributes to the Inflammatory Status of Mature Dendritic Cells 
      through Interleukin-6 Receptor Subunits Modulation.
PG  - 926
LID - 10.3389/fimmu.2017.00926 [doi]
LID - 926
AB  - Tocilizumab, a humanized anti-IL-6 receptor alpha (IL-6Ralpha) 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-6Ralpha 
      (sIL-6Ralpha), and mIL-6Ralpha] 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-6Ralpha expression, and 
      largely increased sIL-6Ralpha secretion. MAPK modulated STAT3 phosphorylation and 
      surface expression of IL-6Ralpha 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-6Ralpha. 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.
FAU - Meley, Daniel
AU  - Meley D
AD  - EA 4245 Cellules Dendritiques, Immuno-modulation et Greffes, Universite 
      Francois-Rabelais de Tours, UFR de Medecine, Tours, France.
FAU - Heraud, Audrey
AU  - Heraud A
AD  - EA 4245 Cellules Dendritiques, Immuno-modulation et Greffes, Universite 
      Francois-Rabelais de Tours, UFR de Medecine, Tours, France.
FAU - Gouilleux-Gruart, Valerie
AU  - Gouilleux-Gruart V
AD  - CNRS UMR 7292; Universite Francois-Rabelais de Tours, UFR de Medecine, Tours, 
      France.
AD  - Department of Immunology, CHRU de Tours, Tours, France.
FAU - Ivanes, Fabrice
AU  - Ivanes F
AD  - EA 4245 Cellules Dendritiques, Immuno-modulation et Greffes, Universite 
      Francois-Rabelais de Tours, UFR de Medecine, Tours, France.
AD  - Service de Cardiologie, CHRU de Tours, Tours, France.
FAU - Velge-Roussel, Florence
AU  - Velge-Roussel F
AD  - EA 4245 Cellules Dendritiques, Immuno-modulation et Greffes, Universite 
      Francois-Rabelais de Tours, UFR de Medecine, Tours, France.
AD  - UFR des Sciences Pharmaceutiques, Tours, France.
LA  - eng
PT  - Journal Article
DEP - 20170816
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
PMC - PMC5561017
OTO - NOTNLM
OT  - IL-6 receptor subunits
OT  - dendritic cell
OT  - inflammation
OT  - rheumatoid arthritis
OT  - tocilizumab
EDAT- 2017/09/02 06:00
MHDA- 2017/09/02 06:01
PMCR- 2017/01/01
CRDT- 2017/09/02 06:00
PHST- 2017/02/21 00:00 [received]
PHST- 2017/07/20 00:00 [accepted]
PHST- 2017/09/02 06:00 [entrez]
PHST- 2017/09/02 06:00 [pubmed]
PHST- 2017/09/02 06:01 [medline]
PHST- 2017/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2017.00926 [doi]
PST - epublish
SO  - Front Immunol. 2017 Aug 16;8:926. doi: 10.3389/fimmu.2017.00926. eCollection 
      2017.