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Increased expression of CCL18, CCL19, and CCL17 by dendritic cells from patients with rheumatoid arthritis, and regulation by Fc gamma receptors

T R D J Radstake¹, R van der Voort², M ten Brummelhuis¹, M de Waal Malefijt³, M Looman², C G Figdor², W B van den Berg¹, P Barrera¹, G J Adema²

¹ Department of Rheumatology, University Medical Centre, Nijmegen, The Netherlands
² Tumour Immunology, University Medical Centre, Nijmegen, The Netherlands
³ Orthopaedic Surgery, University Medical Centre, Nijmegen, The Netherlands

Correspondence to:
Dr T R D J Radstake
Department of Rheumatology/Laboratory of Experimental Rheumatology and Advanced Therapeutics, University Medical Centre Nijmegen, The Netherlands and Nijmegen Centre for Molecular Life Sciences, Geertgroote plein 26–28, 6525 GA Nijmegen, The Netherlands; T.Radstake{at}reuma.umcn.nl

Background: Dendritic cells (DC) have a role in the regulation of immunity and tolerance, attracting inflammatory cells by the production of various chemokines (CK). Fc gamma receptors (FcR) may be involved in regulation of the DC function.

Objective: To assess the expression of CK by immature (iDC) and mature DC (mDC) and its regulation by FcR in patients with RA and healthy donors (HC).

Methods: Expression of CK by DC from patients with RA and from HC was determined by real time quantitative PCR and ELISA. DC were derived from monocytes following standardised protocols. To study the potential regulation by FcR, iDC were stimulated with immune complexes (IC) during lipopolysaccharide (LPS) induced maturation. The presence of CK was studied in synovial tissue from patients with RA, osteoarthritis, and healthy subjects by RT-PCR and immunohistochemistry.

Results: iDC from patients with RA had markedly increased mRNA levels of the CK CCL18 and CXCL8. Upon maturation with LPS, expression of CCL18, CCL19, CXCL8, CCL3, and CCL17 increased dramatically, reaching significantly higher levels in patients with RA. Monocytes failed to express these CK, except for CXCL8 and CCL3. IC-mediated triggering of the FcR on DC from patients with highly active RA down regulated all CK, whereas the reverse was seen when DC from patients with low disease activity and healthy donors were stimulated. CCL18 was significantly increased in RA synovial tissue.

Conclusion: Increased CK expression by DC was found in patients with RA. This expression is partly regulated by FcR triggering and results in an inhibitory DC subtype in RA upon FcR-mediated triggering.

Abbreviations: CK, chemokine(s); DAS28, 28 joint count Disease Activity Score; DC, dendritic cell(s); ELISA, enzyme linked immunosorbent assay; FcR, Fc gammas receptor(s); GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HAGGs, heat aggregated gammaglobulins; HRP, horseradish peroxidase; IC, immune complexes; iDC, immature dendritic cells; IL, interleukin; LPS, lipopolysaccharide; mDC, mature dendritic cells; OA, osteoarthritis; PBGD, porphobilinogen deaminase; PCR, polymerase chain reaction; RA, rheumatoid arthritis; TNF, tumour necrosis factor

Keywords: rheumatoid arthritis; chemokines; dendritic cells; synovial tissue

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