TY - JOUR
T1 - TNF blockade requires 1,25(OH) 2D 3to control human Th17-mediated synovial inflammation
AU - Van Hamburg, Jan Piet
AU - Asmawidjaja, Patrick S.
AU - Davelaar, Nadine
AU - Mus, Adriana M.C.
AU - Cornelissen, Ferry
AU - Van Leeuwen, Johannes P.T.M.
AU - Hazes, Johanna M.W.
AU - Dolhain, Radboud J.E.M.
AU - Bakx, Pieter A.G.M.
AU - Colin, Edgar M.
AU - Lubberts, Erik
PY - 2012/4
Y1 - 2012/4
N2 - Objectives: T helper 17 (Th17) cells from patients with early rheumatoid arthritis (RA) induce a proinflammatory feedback loop upon RA synovial fibroblast (RASF) interaction, including autocrine interleukin (IL)-17A production. A major challenge in medicine is how to control the pathogenic Th17 cell activity in human inflammatory autoimmune diseases. The objective of this study was to examine whether tumour necrosis factor (TNF) blockade and/or 1,25-dihydroxyvitamin D 3 (1,25(OH) 2D 3) controls Th17-mediated synovial inflammation. Methods: Peripheral CD4+CD45RO+CCR6+ Th17 cells of patients with early RA, Th17-RASF cocultures and synovial biopsy specimens were cultured with or without 1,25(OH) 2D 3 and/or TNFα blockade. Intracellular cytokine expression was detected by flow cytometry. Cytokine and matrix metalloprotease (MMP) production was determined by ELISA. Results: The authors show that the 1,25(OH) 2D 3, but not TNFα blockade, significantly suppressed autocrine IL-17A production in Th17-RASF and synovial biopsy cultures. Combining 1,25(OH) 2D 3 and TNFα blockade had a significant additive effect compared with single treatment in controlling synovial inflammation, indicated by a further reduction in IL-6, IL-8, MMP-1 and MMP-3 in Th17-RASF cocultures and IL-6 and IL-8 expression in cultures of RA synovial tissue. Conclusions: These data show that TNF blockade does not suppress IL-17A and IL-22, which can be overcome by 1,25(OH) 2D 3. The combination of neutralising TNF activity and 1,25(OH) 2D 3 controls human Th17 activity and additively inhibits synovial inflammation. This indicates more valuable therapeutic potential of activation of Vitamin D receptor signalling over current TNF neutralisation strategies in patients with RA and potentially other Th17-mediated inflammatory diseases.
AB - Objectives: T helper 17 (Th17) cells from patients with early rheumatoid arthritis (RA) induce a proinflammatory feedback loop upon RA synovial fibroblast (RASF) interaction, including autocrine interleukin (IL)-17A production. A major challenge in medicine is how to control the pathogenic Th17 cell activity in human inflammatory autoimmune diseases. The objective of this study was to examine whether tumour necrosis factor (TNF) blockade and/or 1,25-dihydroxyvitamin D 3 (1,25(OH) 2D 3) controls Th17-mediated synovial inflammation. Methods: Peripheral CD4+CD45RO+CCR6+ Th17 cells of patients with early RA, Th17-RASF cocultures and synovial biopsy specimens were cultured with or without 1,25(OH) 2D 3 and/or TNFα blockade. Intracellular cytokine expression was detected by flow cytometry. Cytokine and matrix metalloprotease (MMP) production was determined by ELISA. Results: The authors show that the 1,25(OH) 2D 3, but not TNFα blockade, significantly suppressed autocrine IL-17A production in Th17-RASF and synovial biopsy cultures. Combining 1,25(OH) 2D 3 and TNFα blockade had a significant additive effect compared with single treatment in controlling synovial inflammation, indicated by a further reduction in IL-6, IL-8, MMP-1 and MMP-3 in Th17-RASF cocultures and IL-6 and IL-8 expression in cultures of RA synovial tissue. Conclusions: These data show that TNF blockade does not suppress IL-17A and IL-22, which can be overcome by 1,25(OH) 2D 3. The combination of neutralising TNF activity and 1,25(OH) 2D 3 controls human Th17 activity and additively inhibits synovial inflammation. This indicates more valuable therapeutic potential of activation of Vitamin D receptor signalling over current TNF neutralisation strategies in patients with RA and potentially other Th17-mediated inflammatory diseases.
UR - http://www.scopus.com/inward/record.url?scp=84857921562&partnerID=8YFLogxK
U2 - https://doi.org/10.1136/annrheumdis-2011-200424
DO - https://doi.org/10.1136/annrheumdis-2011-200424
M3 - Article
C2 - 22219138
SN - 0003-4967
VL - 71
SP - 606
EP - 612
JO - Annals of the rheumatic diseases
JF - Annals of the rheumatic diseases
IS - 4
ER -