Effects of FK506 and other immunosuppressive anti-rheumatic agents on T cell activation mediated IL-6 and IgM production in vitro.
The objective of this study was to investigate the therapeutic potential of FK506 and other immunosuppressive agents for the treatment of rheumatoid arthritis (RA), focusing on the effects on in vitro IL-6 production and IL-6-mediated immune response. We employed an in vitro model producing IL-6 via T cell activation in human PBMC, based on the hypothesis that T cells play a central role in the pathogenesis of RA. FK506 potently inhibited IL-6 production from PBMC stimulated with anti-CD3 and anti-CD28 monoclonal antibody (anti-CD3/CD28). Cyclosporin A (CsA) also inhibited the anti-CD3/CD28 induced IL-6 production but was about 100 times less potent than FK506. Dexamethasone (DEX) inhibited both anti-CD3/CD28 and LPS induced IL-6 production at almost the same concentration. Methotrexate (MTX) did not affect cytokine production. Anti-CD3/CD28 stimulated PBMC culture supernatants were found to enhance IgM production in SKW6.4 cells. The effects of anti-CD3/CD28 stimulated culture supernatants in the presence of agents on IgM production in SKW6.4 cells were investigated. FK506 and CsA led to suppression of IgM production induced by culture supernatants probably via inhibition of IgM inducible cytokine production from PBMC. DEX profoundly enhanced IgM production, although IL-6 production from PBMC was strongly inhibited by the agent. MTX decreased IgM production although it has no inhibitory effect on IL-6 production. The present study suggests that FK506 is the most effective among the four agents for the suppression of IL-6 production and IL-6-mediated autoantibody production in T cell activation related autoimmune diseases such as RA.
Sakuma
S
S
Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co, Ltd, Yodogawa, Osaka, Japan.
Kato
Y
Y
Nishigaki
F
F
Magari
K
K
Miyata
S
S
Ohkubo
Y
Y
Goto
T
T
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D018106:CD28 Antigens / Q000502:physiology; D017252:CD3 Complex / Q000502:physiology; D006801:Humans; D007075:Immunoglobulin M / Q000096:biosynthesis*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008727:Methotrexate / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D016559:Tacrolimus / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018106:CD28 Antigens; D017252:CD3 Complex; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D016559:Tacrolimus; D008727:Methotrexate