Inhibition of TNF-alpha during maturation of dendritic cells (DC) results in the development of semi- mature DC

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Ann Rheum Dis. 2004 Jul 15 [Epub ahead of print]

Inhibition of TNF-{alpha} during maturation of dendritic cells (DC)

results in the development of semi- mature DC: a potential mechanism by

which TNF-{alpha} blockade exerts its benificial effects in rheumatoid

arthritis.

Van Lieshout TW, Barrera P, Smeets RL, Pesman GJ, Van Riel PL, Van Den

Berg WB, Radstake TR.

University Medical Centre Nijmegen, The Netherlands.

OBJECTIVE: Dendritic cells (DC) orchestrate pivotal immunological

processes which are mediated by the production of cytokines and

chemokines. The aim of this study was to assess whether neutralisation

of TNF- & [alpha] during DC maturation affects DC phenotype and

behaviour. This might explain the beneficial effectsof TNF-alpha

neutralisation in rheumatoid arthritis. METHODS: We investigated the

effect of TNF- & [alpha] neutralisation on the phenotype (CD14, CD16,

CD32, CD64, CD80, CD83, CD86 and MHC) of DC by flowcytometry, the

expression of chemokines (CCL17, CCL18, CCL19, CCL22, CCL3 and CXCL8)

and the production of IL-1beta and IL-6 during DC differentiation and

maturation. Immature DC and fully matured DC were cultured from blood

monocytes from RA patients and healthy controls following standardised

protocols and TNF-alpha was neutralised by the addition of PEGsTNF- RI.

Chemokine expression and production of cytokines was measured by

Real-Time PCR, RIA and ELISA techniques. RESULTS: The neutralisation of

TNF-alpha during the differentiation and/or maturation of DC did not

result in an altered DC phenotype, neither in RA patients nor in healthy

controls. In contrast, the expression of CCL17, CCL18, CCL19, CCL22,

CCL3 and CXCL8 by DC was significantly reduced when TNF-alpha activity

was inhibited during LPS triggered maturation of DC. As for chemokine

expression, the production of IL- 1beta and IL-6 by matured DC was

significantly inhibited by PEGsTNF-RI.

CONCLUSION: The inhibition of TNF-alpha activity during DC maturation

lead to the development of semi-mature DC. These data suggest a novel

pathway by which the neutralisation of TNF-alpha might exert its

therapeutic effects. Further research to elucidate the role for

TNF-alpha in DC development in vivo is warranted.

PMID: 15256380

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