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Arthritis Res Ther. 2016 Mar 1;18:56. doi: 10.1186/s13075-016-0955-8.

Anti-TNF certolizumab pegol induces antioxidant response in human monocytes via reverse signaling.

Boyer JF1,2,3, Baron M4,5, Constantin A6,7,8, Degboé Y9,10,11, Cantagrel A12,13,14, Davignon JL15,16,17.

Author information

1
Université Paul Sabatier Toulouse III, Toulouse, France. jeanfred.boyer@gmail.com.
2
INSERM - CNRS U1043, CPTP, CHU Purpan, 1, Place Baylac, 31300, Toulouse, France. jeanfred.boyer@gmail.com.
3
Centre de Rhumatologie, Hopital Pierre Paul Riquet, Toulouse, France. jeanfred.boyer@gmail.com.
4
Université Paul Sabatier Toulouse III, Toulouse, France. michel.baron@inserm.fr.
5
INSERM - CNRS U1043, CPTP, CHU Purpan, 1, Place Baylac, 31300, Toulouse, France. michel.baron@inserm.fr.
6
Université Paul Sabatier Toulouse III, Toulouse, France. arnaud.constantin@univ-tlse3.fr.
7
INSERM - CNRS U1043, CPTP, CHU Purpan, 1, Place Baylac, 31300, Toulouse, France. arnaud.constantin@univ-tlse3.fr.
8
Centre de Rhumatologie, Hopital Pierre Paul Riquet, Toulouse, France. arnaud.constantin@univ-tlse3.fr.
9
Université Paul Sabatier Toulouse III, Toulouse, France. degboe@gmail.com.
10
INSERM - CNRS U1043, CPTP, CHU Purpan, 1, Place Baylac, 31300, Toulouse, France. degboe@gmail.com.
11
Centre de Rhumatologie, Hopital Pierre Paul Riquet, Toulouse, France. degboe@gmail.com.
12
Université Paul Sabatier Toulouse III, Toulouse, France. alain.cantagrel@wanadoo.fr.
13
INSERM - CNRS U1043, CPTP, CHU Purpan, 1, Place Baylac, 31300, Toulouse, France. alain.cantagrel@wanadoo.fr.
14
Centre de Rhumatologie, Hopital Pierre Paul Riquet, Toulouse, France. alain.cantagrel@wanadoo.fr.
15
Université Paul Sabatier Toulouse III, Toulouse, France. jean-luc.davignon@inserm.fr.
16
INSERM - CNRS U1043, CPTP, CHU Purpan, 1, Place Baylac, 31300, Toulouse, France. jean-luc.davignon@inserm.fr.
17
Centre de Rhumatologie, Hopital Pierre Paul Riquet, Toulouse, France. jean-luc.davignon@inserm.fr.

Abstract

BACKGROUND:

Anti TNF drugs have been widely used in rheumatoid arthritis (RA) but only 70 to 80 % of patients respond to this therapy. Exploring the mode of action of anti-TNF drugs remains important in order to improve the efficiency of the treatment and enhance our knowledge of inflammation. TNF-α exists as classical soluble cytokine as well as transmembrane protein (tmTNF-α). Evidence suggests that tmTNF-α can induce reverse signaling. In the present study, we have explored consequences of reverse signaling in human monocytes using certolizumab pegol (CZP).

METHODS:

Monocytes were purified from healthy blood donors and were incubated with CZP. Nuclear translocation of Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) was evaluated by wide-field microscopy and cell fractionation. Heme oxygenase 1 (HO-1) was assessed by RT-qPCR and western blot. Monocytes were stimulated with lipopolysaccharide (LPS). IL-1β was quantitated by RT-qPCR. Reactive oxygen species (ROS) were evaluated by flow cytometry using the H2DCFDA fluorescent marker.

RESULTS:

CZP induced rapid minimal ROS production and Nrf2 nuclear translocation. This was followed by HO-1 mRNA and protein production. IL-1β induction by LPS was inhibited at the mRNA and protein level. At a later time-point, CZP was able to counteract the strong production of ROS induced by LPS. Reverse signaling was suggested by short kinetics of Nrf2 translocation, extensive washing of CZP and the use of anti-TNF-Rs antibodies.

CONCLUSION:

Our data suggest a novel mechanism of ROS modulation by CZP. This observation sheds new light on the function of reverse signaling and on potential mechanisms of action of anti-TNF drugs.

PMID:
26932562
PMCID:
PMC4774095
DOI:
10.1186/s13075-016-0955-8
[Indexed for MEDLINE]
Free PMC Article

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