Title
T cell Signal Transducer and Activator of Transcription (STAT) 4 and 6 are affected by adalimumab therapy in rheumatoid arthritis T cell Signal Transducer and Activator of Transcription (STAT) 4 and 6 are affected by adalimumab therapy in rheumatoid arthritis
Author
Faculty/Department
Faculty of Medicine and Health Sciences
Publication type
article
Publication
Pisa ,
Subject
Human medicine
Source (journal)
Clinical and experimental rheumatology. - Pisa
Volume/pages
28(2010) :2 , p. 208-214
ISSN
0392-856X
ISI
000278303900008
Carrier
E
Target language
English (eng)
Affiliation
University of Antwerp
Abstract
OBJECTIVES: TNF-α inhibition therapy affects the systemic immune response in rheumatoid arthritis by influencing T cell subtypes (Th1, Th2, Treg), but its effect on the intracellular signal transduction in T cells remains largely unexplored. Here we studied the activation of Th1-associated signalling molecule STAT4 and Th2-associated STAT6 in CD4+ T cells. METHODS: Eight rheumatoid arthritis patients were studied before and after 12 weeks of adalimumab therapy and compared to 8 healthy individuals. Peripheral blood mononuclear cells (PBMC) were analysed flow cytometrically either directly after isolation or after 24 hours of anti-CD3/anti-CD28 stimulation, to determine spontaneous and IL-4/IL-12-induced STAT4 and STAT6 phosphorylation in CD4+ T cells. Cytokine production by stimulated PBMC was measured in the supernatant using a cytometric bead array. Non-parametric statistical tests were applied. RESULTS: After adalimumab therapy, phospho-STAT6 increased, both in freshly isolated and anti-CD3/anti-CD28-stimulated CD4+ T cells. The STAT6 response to brief IL-4 stimulation did not change. In healthy individuals and adalimumab-treated patients, anti-CD3/anti-CD28 induced the phosphorylation of STAT4, but not in untreated patients. IFN-γ production in untreated patients was significantly lower than in healthy individuals or adalimumab-treated patients. In contrast, the production of IL-4, IL-6 and IL-12 was not influenced. CONCLUSIONS: Adalimumab therapy increases Th2-associated STAT6 phosphorylation and restores the activation-induced STAT4 phosphorylation to the levels in healthy individuals. This advocates against a pro-inflammatory effect of Th1-associated STAT4 and might provide an explanation for the influence of TNF inhibition therapy on the systemic T cell response in rheumatoid arthritis.
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