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

Rheumatology (Oxford). 2000 Jun;39(6):637-45. doi: 10.1093/rheumatology/39.6.637.


Objective: 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).

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 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.

Results: 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.

Conclusions: 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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arthritis, Rheumatoid / blood
  • Arthritis, Rheumatoid / drug therapy
  • Arthritis, Rheumatoid / metabolism*
  • Female
  • Humans
  • Immunosuppressive Agents / therapeutic use
  • Interleukin-6 / blood
  • Leukocytes, Mononuclear / drug effects*
  • Leukocytes, Mononuclear / metabolism
  • Male
  • Matrix Metalloproteinase 1 / blood
  • Methotrexate / therapeutic use*
  • Middle Aged
  • Tissue Inhibitor of Metalloproteinase-1 / biosynthesis
  • Tissue Inhibitor of Metalloproteinase-1 / blood*


  • Immunosuppressive Agents
  • Interleukin-6
  • Tissue Inhibitor of Metalloproteinase-1
  • Matrix Metalloproteinase 1
  • Methotrexate