Enhanced production of tissue inhibitor of metalloproteinases by peripheral blood mononuclear cells of rheumatoid arthritis patients responding to methotrexate treatment.

Abstract

To determine the effects of methotrexate (MTX) treatment of rheumatoid arthritis (RA) patients (a) on the circulating levels and (b) on the ex vivo production of matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinases-1 (TIMP-1) by peripheral blood mononuclear cells (PBMNC). Circulating levels, spontaneous ex vivo and in vitro production of MMP-1, TIMP-1 and interleukin-6 (IL-6) were assessed by immunoassays in sera and culture supernatants of PBMNC derived from 27 patients with active RA before and 3 months after beginning MTX treatment and from seven healthy subjects. The production and serum levels of MMP-1, TIMP-1 and IL-6 were correlated to the clinical response. PBMNC of RA patients showing >/= 20% improvement of the Paulus index after 3 months of MTX treatment (responders; n = 16) exhibited a significantly enhanced production of spontaneous TIMP-1 ex vivo which was associated with the enhanced synthesis of IL-6. In contrast, PBMNC of 11 patients with <20% improvement and/or progression of disease showed a marked reduction of TIMP-1 and IL-6 secretion. Circulating levels of TIMP-1 remained unchanged in both groups whereas serum IL-6 levels declined in the responder group. MMP-1 was detectable only in very few culture supernatants and RA sera. Moreover, PBMNC of healthy donors revealed that MTX also stimulated TIMP-1 and IL-6 release in vitro, IL-6 being partially responsible for the induction of TIMP-1 production. Both ex vivo and in vitro, the enhanced TIMP-1 production by PBMNC of RA patients and healthy individuals upon MTX treatment is associated with simultaneously enhanced IL-6 release, and enhanced ex vivo production of both is clearly associated with short-term clinical efficacy. This may reflect disease remission and favourable effects on host defence mechanisms against aberrant inflammation and extracellular matrix turnover in RA patients undergoing MTX treatment.