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Annals of the Rheumatic Diseases 2004;63:696-702
© 2004 by BMJ Publishing Group Ltd & European League Against Rheumatism

EXTENDED REPORT

High production of proinflammatory and Th1 cytokines by dendritic cells from patients with rheumatoid arthritis, and down regulation upon Fc{gamma}R triggering

T R D J Radstake 1, P L E M van Lent 1, G J Pesman 2, A B Blom 1, F G J Sweep 2, J Rönnelid 3, G J Adema 4, P Barrera 1, W B van den Berg 1

1 Department of Experimental Rheumatology, University Medical Centre, Nijmegen, The Netherlands
2 Experimental and Chemical Endocrinology, University Medical Centre, Nijmegen, The Netherlands
3 Clinical Immunology, Autoimmunity and Allergy, University Hospital Uppsala, Sweden
4 Tumour Immunology Laboratory, University Medical Centre, Nijmegen, The Netherlands

Correspondence to:
Correspondence to:
Dr T R D J Radstake
Geert Grooteplein 8, 6500 HB Nijmegen, The Netherlands; T.Radstake{at}reuma.umcn.nl

Objective: To assess whether DC from RA produce altered cytokine levels and whether this is regulated by triggering of Fc gamma receptors (Fc{gamma}R).

Methods: The production of proinflammatory (TNF{alpha}, IL1, IL6), Th1 (IL12, IFN{gamma}), and Th2 (IL10) cytokine profiles of immature DC (iDC) from patients with RA and healthy subjects upon triggering of Fc{gamma}R dependent and independent pathways was investigated. iDC, derived from blood monocytes by standardised protocols, were stimulated with immune complexes (IC) at day 6 for 48 hours and, subsequently, for 2 days with LPS in the presence or absence of IC or IFN{gamma}, resulting in fully matured DC (mDC). IL1, IL6, TNF{alpha}, IFN{gamma}, IL12, and IL10 levels in supernatants were measured by ELISA and RIA.

Results: mDC from patients with RA showed a markedly increased production of IL1, IL6, TNF{alpha}, and IL10 compared with DC from healthy donors. Triggering of Fc{gamma}R decreased the production of proinflammatory cytokines IL1, IL12, and IFN{gamma} by iDC and mDC in RA and controls. The production of IL6 and TNF{alpha} decreased in patients with RA, whereas it was increased in controls. Triggering of Fc{gamma}R independent mechanisms using IFN{gamma} increased the production of proinflammatory and Th1 cytokines, which was more pronounced in RA.

Conclusion: Fc{gamma}R dependent pathways influence cytokine production by DC. A skewed balance towards proinflammatory and Th1 cytokines in RA can, at least partly, be restored by triggering Fc{gamma}R on DC in RA. Insight into the mechanism which determines the Fc{gamma}R balance might lead to new strategies to abrogate Th1 driven inflammatory processes in RA.

Keywords: dendritic cells; Fc gamma receptor; tumour necrosis factor; interleukin 10; interleukin 12

Abbreviations: DC, dendritic cells; ELISA, enzyme linked immunosorbent assay; FACS, fluorescence activated cell sorter; Fc{gamma}R, Fc gamma receptor; HAGGS, heat aggregated gamma immunoglobulins; IC, immune complexes; iDC, immature dendritic cells; IFN{gamma}, interferon {gamma}; IL, interleukin; LPS, lipopolysaccharide; mDC, mature dendritic cells; RA, rheumatoid arthritis; RIA, radioimmunoassay; TNF{alpha}, tumour necrosis factor {alpha}




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