Monocytes are essential for inhibition of synovial T-cell glucocorticoid-mediated apoptosis in rheumatoid arthritis.
BACKGROUND
Rheumatoid arthritis (RA) is characterized by synovial inflammation with local accumulation of mononuclear cells such as macrophages and lymphocytes. We previously demonstrated that intra-articular glucocorticoids decrease the synovial tissue (ST) T-cell population and therefore aimed to investigate whether this is mediated through modulation of apoptosis.


METHODS
Apoptosis and cell phenotype were evaluated by immunohistochemistry and dual-immunofluorescence in synovial biopsy sections from 12 RA patients before and after a mean of 11 days of an intra-articular triamcinolone knee injection. In vitro, RA synovial fluid (SF)-derived T cells were evaluated for Annexin V expression by multicolor flow cytometry after 24-hour exposure to dexamethasone, methylprednisolone, or triamcinolone. We also tested induction of apoptosis by dexamethasone on psoriatic arthritis SF-derived T cells using the same method.


RESULTS
Intra-articular glucocorticoids reduced ST T cells but not macrophage number. ST apoptosis levels were unchanged following treatment, virtually absent from lymphoid aggregates, and minimal in CD3+ cells both before and after treatment. RA SF T cells were resistant to glucocorticoid-induced apoptosis when cultured in the presence of monocytes but were rendered sensitive to all three tested compounds upon SF isolation. Furthermore, transwell coculture of monocytes and T cells demonstrated that soluble factor(s) and not cellular contact are essential for T-cell resistance to glucocorticoid-mediated apoptosis. This feature is RA-specific as far as dexamethasone-induced apoptosis in nonisolated SF T cells obtained from psoriatic arthritis patients is concerned.


CONCLUSIONS
We demonstrate that monocytes rescue synovial T cells from glucocorticoid-induced apoptosis, a feature that is specific for RA. To overcome this, we propose the use of monocyte-targeted therapies rather than T-cell apoptosis-inducing therapies.
Makrygiannakis
Dimitrios
D
Department of Rheumatology, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden. dimitris.makrygiannakis@ki.se
Revu
Shankar
S
Neregård
Petra
P
af Klint
Erik
E
Snir
Omri
O
Grundtman
Cecilia
C
Catrina
Anca Irinel
AI
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D005260:Female; D005938:Glucocorticoids / Q000633:toxicity*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D013582:Synovial Fluid / Q000187:drug effects / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D005938:Glucocorticoids