A review of the action of tacrolimus (FK506) on experimental models of rheumatoid arthritis

Abstract

Tacrolimus (FK506) is an immunosuppressive drug, widely used for organ transplantation and atopic dermatitis. Tacrolimus exerts its immunosuppressive effects primarily by interfering with the activation of T cells, via inhibition of calcineurin. Recent clinical studies have also demonstrated the efficacy of tacrolimus in the treatment of rheumatoid arthritis (RA), an autoimmune disease in which T cells play a pivotal role in pathogenesis. Inflammatory cytokines such as TNF-alpha, IL-1 beta, and IL-6 are involved in development of the disease. Recently, modes of action of tacrolimus on RA have been intensively studied in in vitro and animal arthritis models, demonstrating that tacrolimus exerts various novel actions as an anti-rheumatic drug. The pharmacological action of tacrolimus suggests that it has potential to specifically suppress the production of pathogenic inflammatory cytokines with a low frequency of infection, improve joint inflammation and bone/cartilage destruction, fully recover loss of functional status, exert rapid relief in arthritic pain, and promote osteogenic and chondrogenic differentiation. Here we review the action of tacrolimus on experimental models of RA, with a focus on our recent studies, and provide further insight into experimental models used for identifying efficacious anti-rheumatic drugs.

Tacrolimus regulates endoplasmic reticulum stress–mediated osteoclastogenesis and inflammation: In vitro and collagen‐induced arthritis mouse model

“…TAC acts by binding to specific intracellular proteins. The formed complex inhibits calcineurin phosphatase, which prevents the activation of the transcription factor NF‐AT required for the production of cytokines, such as IL‐2 and γ‐interferon (Miyata et al, ). A clinical trial with TAC showed the advantages of combining it with MTX in treating patients with an inadequate response to MTX monotherapy (Kremer et al, ; Yocum et al, ; Kawai and Yamamoto, ).…”

Effect of tacrolimus and cyclosporine A on suppression of albumin secretion induced by inflammatory cytokines in cultured human hepatocytes

“…CSA and FK506 have been employed in clinical graft-versus-host rejection after solid organ and bone-marrow transplantation over the past two decades. FK506 was recently approved in the USA for the treatment and prevention of immune-related diseases such as immune glomerulonephritis and rheumatoid arthritis [8,19]. A clinical study reported that FK506 could increase the level of serum albumin and reduce the level of urinary protein in the treatment of diffuse proliferative glomerulonephritis in associated with systemic lupus erythematosus [8].…”

Simultaneous determination of three isomeric metabolites of tacrolimus (FK506) in human whole blood and plasma using high performance liquid chromatography–tandem mass spectrometry

“…This compound has also been introduced to treat atopic dermatitis for several years [4][5][6]. Some other new indications and applications of tacrolimus have been investigated as well [7,8]. There are quite a few published * Corresponding author.…”