FK506 inhibition of gliostatin/thymidine phosphorylase production induced by tumor necrosis factor-α in rheumatoid fibroblast-like synoviocytes.
Gliostatin/thymidine phosphorylase (GLS/TP) is known to have angiogenic and arthritogenic activities. The purpose of this study was to determine the inhibitory effects of FK506 (tacrolimus) on GLS production in rheumatoid arthritis (RA). We investigated the modulation of serum GLS by FK506 therapy and the effect of FK506 on the production of GLS in fibroblast-like synoviocytes (FLSs). Serum samples were collected from 11 RA patients with active disease at baseline and after 12 weeks of FK506 treatment. Serum concentrations of GLS and matrix metalloproteinase (MMP)-3 were measured by ELISA and found to be down-regulated in responders evaluated with a disease activity score. Patient FLSs were cultured and stimulated by tumor necrosis factor (TNF)-α with or without FK506. The expression levels of GLS were determined using reverse transcription-polymerase chain reaction (RT-PCR) and enzyme immunoassay and shown to be significantly increased. GLS levels in TNF-α-stimulated FLSs were reduced by FK506 treatment. Our data show a novel mechanism for the action of physiological concentrations of FK506 in RA that regulates the production of GLS in FLSs.
Department of Orthopaedic Surgery, Nagoya City University Graduate School of Medical Sciences, Mizuho-Ku, Nagoya, 467-8601, Japan.
Takaya
T
Yamagami
Yuko
Y
Waguri-Nagaya
Kenji
K
Ikuta
Mineyoshi
M
Aoyama
Kiyofumi
K
Asai
Takanobu
T
Otsuka
D000368:Aged; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D013583:Synovial Membrane / Q000201:enzymology / Q000473:pathology; D016559:Tacrolimus / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; C543750:TYMP protein, human; D013939:Thymidine Phosphorylase; D016559:Tacrolimus