First Release: The Functional Variant (Asp299gly) of Toll-like Receptor 4 (TLR4) Influences TLR4-Mediated Cytokine Production in Rheumatoid Arthritis

The Functional Variant (Asp299gly) of Toll-like Receptor 4 (TLR4) Influences TLR4-Mediated Cytokine Production in Rheumatoid Arthritis

MIEKE F. ROELOFS, MARK H. WENINK, ERIK J.M. TOONEN, MARIEKE J.H. COENEN, LEO A.B. JOOSTEN, WIM B. van den BERG, PIET L.C.M. van RIEL, and TIMOTHY R.D.J. RADSTAKE

ABSTRACT.

Objective. To investigate functional consequences of the Toll-like receptor 4 (TLR4) variant (Asp299Gly) in rheumatoid arthritis (RA).

Methods. Peripheral blood mononuclear cells from 28 patients with RA carrying or not carrying the TLR4 variant were incubated with lipopolysaccharide (LPS) and heat shock protein B8 (HSPB8). Concentrations of interleukin 6 (IL-6), tumor necrosis factor-a (TNF-a), and IL-10 were determined along with TLR4 and CD14 expression.

Results. TLR4 expression was similar in patients carrying or not carrying the variant. In contrast, both LPS and HSPB8 resulted in significantly lower secretion of IL-6, TNF-a, and IL-10 in those who carried the variant, whereas the frequency of CD14+ cells was higher in these individuals.

Conclusion. TLR4 variant clearly reduces its potency to mediate signaling. Correction for CD14+ cells is necessary in comparable experiments. (J Rheumatol First Release Mar 15 2008)

Key Indexing Terms:

TOLL-LIKE RECEPTORS
RHEUMATOID ARTHRITIS
DENDRITIC CELLS

From the Department of Rheumatology and Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; and The Arthritis Center, Boston, Massachusetts, USA.

Supported by the National Organization of Research (NWO, VENI grant, Dr. Radstake) and the European League Against Rheumatism (EULAR, Young Investigator awards, Dr. Radstake).

M.F. Roelofs, PhD; M.H. Wenink, MD; L.A.B. Joosten, PhD; W.B. van den Berg, PhD, Professor; P.L.C.M. van Riel, MD, PhD, Professor, Department of Rheumatology; E.J.M. Toonen, MSc; M.J.H. Coenen, PhD, Department of Human Genetics, Radboud University Nijmegen Medical Centre; T.R.D.J. Radstake, MD, PhD, Department of Rheumatology, Radboud University Nijmegen Medical Centre, The Netherlands. Current address: The Arthritis Center, Boston University Medical Center, Boston, MA, USA.

Address reprint requests to Dr. T.R.D.J. Radstake, Department of Rheumatology, Radboud University Nijmegen, Medical Centre, Geert Grooteplein 8, 6500 HB Nijmegen, The Netherlands. E-mail: t.radstake@reuma.umcn.nl

Accepted for publication November 21, 2007.