Inhibition of TNF alpha during maturation of dendritic cells results in the development of semi-mature cells: a potential mechanism for the beneficial effects of TNF alpha blockade in rheumatoid arthritis.
BACKGROUND
Dendritic cells orchestrate pivotal immunological processes mediated by the production of cytokines and chemokines.


OBJECTIVE
To assess whether neutralisation of tumour necrosis factor alpha (TNF alpha) during maturation of dendritic cells affects their phenotype and behaviour, which might explain the beneficial effects of TNF alpha neutralisation in rheumatoid arthritis.


METHODS
Immature and fully matured dendritic cells were cultured from blood monocytes from patients with rheumatoid arthritis and healthy controls following standardised protocols. TNF alpha was neutralised by addition of the p55 soluble TNF alpha receptor, PEGsTNFRI. The effect of TNF alpha neutralisation on the phenotype (CD14, CD16, CD32, CD64, CD80, CD83, CD86, and MHC) of dendritic cells was investigated by flow cytometry. Expression of chemokines (CCL17, CCL18, CCL19, CCL22, CCL3, and CXCL8) and production of IL1 beta and IL6 during dendritic cell differentiation and maturation were examined.


RESULTS
Neutralisation of TNF alpha during the differentiation and maturation of dendritic cells did not result in an altered dendritic cell phenotype in the rheumatoid patients or the healthy controls. In contrast, the expression of CCL17, CCL18, CCL19, CCL22, CCL3, and CXCL8 by dendritic cells was significantly reduced when TNF alpha activity was inhibited during lipopolysaccharide triggered dendritic cell maturation. The production of IL1 beta and IL6 by mature dendritic cells was inhibited by PEGsTNFRI.


CONCLUSIONS
Inhibition of TNF alpha activity during dendritic cell maturation leads to the development of semi-mature cells. These data suggest a novel pathway by which the neutralisation of TNF alpha might exert its therapeutic effects.
van Lieshout
A W T
AW
Department of Rhumatology, University Medical Centre Nijmegen, Geert Grooteplein 8, 6500 HB Nijmegen, Netherlands.
Barrera
P
P
Smeets
R L
RL
Pesman
G J
GJ
van Riel
P L C M
PL
van den Berg
W B
WB
Radstake
T R D J
TR
D001172:Arthritis, Rheumatoid / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D019742:Chemokines, CC / Q000097:blood; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D016130:Immunophenotyping; D007375:Interleukin-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D011092:Polyethylene Glycols / Q000494:pharmacology; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000502:physiology
D019742:Chemokines, CC; D007375:Interleukin-1; D015850:Interleukin-6; C496217:PEGylated tumor necrosis factor alpha receptor 1; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D011092:Polyethylene Glycols