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Increased Nuclear Factor-kB Activation in Peripheral Blood Monocytes of Patients with Rheumatoid Arthritis Is Mediated Primarily by Tumor Necrosis Factor-a

ISABELLE DICHAMP, ALAIN BOURGEOIS, CARINE DIRAND, GEORGES HERBEIN, and DANIEL WENDLING

ABSTRACT.

Objective. Rheumatoid arthritis (RA) is a disease characterized by prolonged production of tumor necrosis factor-a (TNF-a), which is regulated by the Rel/nuclear factor-kB (NF-kB) transcription factors. We assessed NF-kB activation in peripheral blood mononuclear cells (PBMC), peripheral blood lymphocytes (PBL), and monocytes from patients with RA, patients with ankylosing spondylitis (AS), and healthy subjects.

Methods. NF-kB activation was determined by electrophoretic mobility shift assays and by Western blotting in PBMC, monocytes, and PBL isolated from peripheral blood of patients with RA, patients with AS, and healthy subjects and determined after ex vivo pretreatment of PBMC, PBL, and monocytes of patients with RA and healthy subjects with infliximab and with etanercept.

Results. Enhanced NF-kB activation was observed in monocytes, PBL, and PBMC isolated from patients with RA, but not in PBMC, PBL, and monocytes of patients with AS and healthy subjects. The NF-kB complex was composed of p50 and p65 subunits and its activation required inhibitor of NF-kBa degradation. We observed a positive correlation between the NF-kB activation in monocytes, PBL, and PBMC, and TNF-a levels in peripheral blood of patients with RA. Ex vivo treatment with infliximab and etanercept decreased NF-kB activation in monocytes of patients with RA, but not in PBL and PBMC, and not in healthy subjects.

Conclusion. Our results indicate a role for NF-kB activation and TNF-a in the activation of monocytes of patients with RA, and suggest an important role of circulating monocytes in RA pathogenesis. (First Release Sept 15 2007; J Rheumatol 2007;34:1976-83)

Key Indexing Terms:

MONOCYTES
NUCLEAR FACTOR-kB
RHEUMATOID ARTHRITIS
TUMOR NECROSIS FACTOR-a

From the Departments of Virology and Rheumatology, CHU Besançon, Franche-Comté University, Besançon, France.

I. Dichamp, PhD; A. Bourgeois, Technician; C. Dirand, Technician; G. Herbein, MD, PhD, Department of Virology; D. Wendling, MD, PhD, Department of Rheumatology, CHU Besançon, Franche-Comté University.

Address reprint requests to Dr. G. Herbein, Department of Virology, CHU Saint-Jacques de Besançon, Franche-Comté University, 2 Place Saint-Jacques, 25030 Besançon Cedex, France. E-mail: gherbein@chu-besancon.fr

Accepted for publication July 27, 2007.