TY - JOUR
T1 - Synovial fibroblasts directly induce TH17 pathogenicity via the cyclooxygenase/prostaglandin E2 pathway, independent of IL-23
AU - Paulissen, Sandra M.J.
AU - Van Hamburg, Jan Piet
AU - Davelaar, Nadine
AU - Asmawidjaja, Patrick S.
AU - Hazes, Johanna M.W.
AU - Lubberts, Erik
PY - 2013/8/1
Y1 - 2013/8/1
N2 - Th17 cells are critically involved in autoimmune disease induction and severity. Recently, we showed that Th17 cells from patients with rheumatoid arthritis (RA) directly induced a proinflammatory loop upon interaction with RA synovial fibroblasts (RASF), including increased autocrine IL-17A production. To unravel the mechanism driving this IL-17A production, we obtained primary CD4+CD45RO+CCR6+ (Th17) cells and CD4+CD45RO+CCR62 (CCR62) T cells from RA patients or healthy individuals and cocultured these with RASF. IL-1b, IL-6, IL-23p19, and cyclooxygenase (COX)-2 expression and PGE2 production in Th17-RASF cultures were higher than in CCR62 T cell-RASF cultures. Cytokine neutralization showed that IL-1b and IL-6, but not IL-23, contributed to autocrine IL-17A induction. Importantly, treatment with celecoxib, a COX-2 inhibitor, resulted in significantly lower PGE2 and IL-17A, but not IFN-g, production. Combined celecoxib and TNF-A blockade more effectively suppressed the proinflammatory loop than did single treatment, as shown by lower IL-6, IL-8, matrix metalloproteinase-1 and matrix metalloproteinase-3 production. These findings show a critical role for the COX-2/PGE2 pathway in driving Th17-mediated synovial inflammation in an IL-23- and monocyte-independent manner. Therefore, it would be important to control PGE2 in chronic inflammation in RA and potentially other Th17-mediated autoimmune disorders.
AB - Th17 cells are critically involved in autoimmune disease induction and severity. Recently, we showed that Th17 cells from patients with rheumatoid arthritis (RA) directly induced a proinflammatory loop upon interaction with RA synovial fibroblasts (RASF), including increased autocrine IL-17A production. To unravel the mechanism driving this IL-17A production, we obtained primary CD4+CD45RO+CCR6+ (Th17) cells and CD4+CD45RO+CCR62 (CCR62) T cells from RA patients or healthy individuals and cocultured these with RASF. IL-1b, IL-6, IL-23p19, and cyclooxygenase (COX)-2 expression and PGE2 production in Th17-RASF cultures were higher than in CCR62 T cell-RASF cultures. Cytokine neutralization showed that IL-1b and IL-6, but not IL-23, contributed to autocrine IL-17A induction. Importantly, treatment with celecoxib, a COX-2 inhibitor, resulted in significantly lower PGE2 and IL-17A, but not IFN-g, production. Combined celecoxib and TNF-A blockade more effectively suppressed the proinflammatory loop than did single treatment, as shown by lower IL-6, IL-8, matrix metalloproteinase-1 and matrix metalloproteinase-3 production. These findings show a critical role for the COX-2/PGE2 pathway in driving Th17-mediated synovial inflammation in an IL-23- and monocyte-independent manner. Therefore, it would be important to control PGE2 in chronic inflammation in RA and potentially other Th17-mediated autoimmune disorders.
UR - http://www.scopus.com/inward/record.url?scp=84880664114&partnerID=8YFLogxK
U2 - https://doi.org/10.4049/jimmunol.1300274
DO - https://doi.org/10.4049/jimmunol.1300274
M3 - Article
C2 - 23817417
SN - 0022-1767
VL - 191
SP - 1364
EP - 1372
JO - Journal of Immunology
JF - Journal of Immunology
IS - 3
ER -