NDLI: Synovial fibroblasts directly induce Th17 pathogenicity via the cyclooxygenase/prostaglandin E2 pathway, independent of IL-23.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Lubberts, Erik Van Hamburg, Jan Piet Asmawidjaja, Patrick S. Paulissen, Sandra M. J. Davelaar, Nadine Hazes, Johanna M. W.
Description	Country affiliation: Netherlands Author Affiliation: Paulissen SM ( Department of Rheumatology, Erasmus University Medical Center, Erasmus University, 3000 DR Rotterdam, The Netherlands.)
Abstract	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(+)CCR6(-) (CCR6(-)) T cells from RA patients or healthy individuals and cocultured these with RASF. IL-1ß, IL-6, IL-23p19, and cyclooxygenase (COX)-2 expression and PGE2 production in Th17-RASF cultures were higher than in CCR6(-) T cell-RASF cultures. Cytokine neutralization showed that IL-1ß 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-Î³, production. Combined celecoxib and TNF- 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.
ISSN	00221767
e-ISSN	15506606
Journal	The Journal of Immunology
Issue Number	3
Volume Number	191
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2013-08-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Arthritis, Rheumatoid Metabolism Cyclooxygenase 2 Dinoprostone Th17 Cells Antigens, Cd4 Antigens, Cd45 Immunology Celecoxib Cells, Cultured Cyclooxygenase 2 Inhibitors Pharmacology Fibroblasts Inflammation Interferon-gamma Biosynthesis Interleukin-17 Interleukin-1beta Interleukin-23 Subunit P19 Interleukin-6 Interleukin-8 Matrix Metalloproteinase 1 Matrix Metalloproteinase 3 Pyrazoles Receptors, Ccr6 Sulfonamides Synovial Membrane Cytology Tumor Necrosis Factor-alpha Antagonists & Inhibitors Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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