Abstract
OBJECTIVE: To investigate the effect of in vivo treatment with methotrexate (MTX) on the regulation of ex vivo interleukin 10 (IL-10) production by peripheral blood mononuclear cells (PBMC) derived from patients with rheumatoid arthritis (RA). METHODS: Spontaneous as well as lipopolysaccharide (LPS) and phytohemagglutinin (PHA) induced IL-10 release was assessed by a specific immunoassay in culture supernatants of PBMC derived from 32 patients with active RA before and 6, 12, and 24 weeks after MTX treatment. IL- 10 production was correlated to the clinical response. As a control, IL-10 release from PBMC of 7 healthy blood donors was determined. RESULTS: PBMC of patients with RA showing > 50% improvement of the Paulus index after 3 and 6 months of MTX treatment (responders; n = 18) exhibited significantly enhanced IL-10 production after in vitro stimulation with LPS, whereas constitutively released IL-10 was below the detection limit of the immunoassay in all patients and controls. In contrast, IL-10 release from LPS stimulated PBMC of RA patients who showed < 20% improvement by Paulus index (nonresponders; n = 14) or who even deteriorated compared to baseline disease activity was markedly downregulated during MTX treatment in vivo. PHA-induced IL-10 release from PBMC in vitro was not significantly affected by MTX in vivo whether RA patients responded or not to MTX. CONCLUSION: Enhanced ex vivo LPS induced IL-10 production by PBMC of patients with RA is associated with a favorable therapeutic response to MTX treatment, whereas reduced production coincides more closely with disease deterioration or insufficient response. This may reflect both disease outcome upon treatment and/or the mode of the antiinflammatory action of MTX in RA. Because the LPS--but not the PHA--induced ex vivo IL-10 production by PBMC was stimulated by MTX in vivo, monocytes seem to be the prominent target cells for this drug mediated antiinflammatory cytokine regulation.
