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

Objective. To determine the effects of methotrexate (MTX) treatment of rheu matoid arthritis (RA) patients (a) on the circulating levels and (b) on the ex vivo production of matrix metalloproteinase-1 (MMP-1) and tissue inhibi tor of metalloproteinases-1 (TIMP-1) by peripheral blood mononuclear cells (PBMNC). Methods. Circulating levels, spontaneous ex vivo and in vitro production of MMP-1, TIMP-1 and interleukin-6 (IL-6) were assessed by immunoassays in se ra and culture supernatants of PBMNC derived from 27 patients with active R A 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 co rrelated to the clinical response. Results. PBMNC of RA patients showing greater than or equal to 20% improvem ent of the Paulus index after 3 months of MTX treatment (responders; n = 16 ) exhibited a significantly enhanced production of spontaneous TIMP-1 ex vi vo which was associated with the enhanced synthesis of IL-6. In contrast, P BMNC of 11 patients with <20% improvement and/or progression of disease sho wed 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 supe rnatants and RA sera. Moreover, PBMNC of healthy donors revealed that MTX a lso stimulated TIMP-1 and IL-6 release in vitro, IL-6 being partially respo nsible for the induction of TIMP-1 production. Conclusions. Both ex vivo and in vitro, the enhanced TIMP-1 production by P BMNC of RA patients and healthy individuals upon MTX treatment is associate d with simultaneously enhanced IL-6 release, and enhanced ex vivo productio n of both is clearly associated with short-term clinical efficacy. This may reflect disease remission and favourable effects on host defence mechanism s against aberrant inflammation and extracellular matrix turnover in RA pat ients undergoing MTX treatment.