IL-1 beta- and IL-4-induced down-regulation of autotaxin mRNA and PC-1 in fibroblast-like synoviocytes of patients with rheumatoid arthritis (RA)

Autotaxin (ATX) is a 125-kD ectonucleotide pyrophosphate/phosphodiesterase, which was initially isolated and cloned from human melanoma cells as a pot ent stimulator of tumour cell motility. ATX shows 44% identity to the plasm a cell membrane marker PC-1. Recently, we described the decreased expressio n of ATX mRNA in cultured fibroblast-like synoviocytes (SFC) of patients wi th RA by interferon-gamma. In this study using a competitive reverse transc riptase-polymerase chain reaction, we show an increased ATX mRNA expression in SFC from patients with RA in comparison with synoviocytes from non-RA p atients. The median ATX mRNA amount in SFC of RA patients (440 pg/mug total RNA) was five-fold higher than the expression in synoviocytes from non-RA patients (80 pg/mug total RNA) or foreskin fibroblasts (MRHF cells, 90 pg/m ug total RNA). In contrast to the elevated ATX mRNA expression in SFC of pa tients with RA, we did not measure increased mRNA amounts of PC-1 in these cells. Both the ATX mRNA amount and the 5'-nucleotide phosphodiesterase (PD E) activity of SFC lysate were reduced after treatment of SFC with the cyto kines IL-1 beta or IL-4. IL-1 beta and IL-4 induced a down-regulation of PC -1 mRNA and protein expression in SFC. In SFC treated with transforming gro wth factor-beta the expression of PC-1 mRNA and protein was increased, wher eas no significant effect on ATX mRNA expression was detectable. Pharmacolo gical drugs used in therapy for RA, such as dexamethasone, cyclosporin, met hotrexate and indomethacin, did not show a statistically significant effect on either ATX mRNA or PC-1 mRNA expression. Only pentoxifylline suppressed ATX mRNA as well as PC-1 mRNA expression. In conclusion, we show a tight r egulation of ATX and PC-1 gene expression by cytokines detectable in the in flamed tissue of RA. Further investigations will deal with the regulation o f ATX protein expression as well as with the function of ATX in RA.