Seitz M, Zwicker M, Wider B
Department of Rheumatology and Clinical Immunology/Allergology, University Hospital, Inselspital, Bern, Switzerland.
J Rheumatol. 2001 Mar;28(3):496-501.
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).
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.
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.
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.
研究甲氨蝶呤（MTX）体内治疗对类风湿关节炎（RA）患者外周血单个核细胞（PBMC）体外白细胞介素10（IL-10）产生调节的影响。
采用特异性免疫测定法评估32例活动期RA患者在MTX治疗前及治疗后6、12和24周时PBMC培养上清液中自发以及脂多糖（LPS）和植物血凝素（PHA）诱导的IL-10释放。将IL-10产生与临床反应相关联。作为对照，测定7名健康献血者PBMC的IL-10释放。
MTX治疗3个月和6个月后Paulus指数改善>50%的RA患者（反应者；n = 18）的PBMC在体外经LPS刺激后IL-10产生显著增强，而所有患者和对照中组成性释放的IL-10均低于免疫测定的检测限。相反，Paulus指数改善<20%的RA患者（无反应者；n = 14）或与基线疾病活动相比病情甚至恶化的患者，其LPS刺激的PBMC在MTX体内治疗期间IL-10释放明显下调。无论RA患者对MTX有无反应，体内MTX对体外PBMC中PHA诱导的IL-10释放均无显著影响。
RA患者PBMC体外LPS诱导的IL-10产生增强与对MTX治疗的良好治疗反应相关，而产生减少则与疾病恶化或反应不足更密切相关。这可能反映了治疗后的疾病结局和/或MTX在RA中的抗炎作用模式。由于体内MTX刺激了PBMC体外LPS诱导而非PHA诱导的IL-10产生，单核细胞似乎是这种药物介导的抗炎细胞因子调节的主要靶细胞。
