CYTOKINE SECRETION AND NITRIC-OXIDE PRODUCTION BY MONONUCLEAR-CELLS OF PATIENTS WITH MULTIPLE-SCLEROSIS

Several experimental findings suggest a potential role of excessive ni tric oxide (NO) production by macrophages, microglia and astrocytes in the pathogenesis of demyelinating lesions in MS. We assessed the prod uction of nitrites by peripheral blood mononuclear cells (PBMCs) of 15 MS patients (10 F and 5 M) with the R-R form (EDSS: 1-3.0) and in 15 age-matched control subjects. 9 out of the 15 MS patients showed activ e lesions in MRI at the time of examination. 7 patients were also moni tored at the onset, during and following a clinical relapse. Secretion of cytokines by PBMCs was assessed at the basal time and after 24 h o f incubation with lipopolysaccharide (LPS). The production of nitrites in the supernatants of PBMCs stimulated and not stimulated with lipop olysaccharide was evaluated. The secretion of IL1 beta, IFN-gamma, TNF -alpha, IL-6 IL-10 and TGF-beta by PBMCs was detected using ELISA meth ods. The production of NO, both basal and stimulated, was significantl y higher in the patients with active lesions than in these without act ive lesions (p < 0.01). No significant difference was evident between the basal and LPS-stimulated production of NO between control subjects and MS patients without active lesions. During relapses there was a s ignificant increase in NO production by PBMCs compared to the clinical stable stage of the disease (p < 0.0001). This increase was significa ntly greater in the early stage of relapse than in the late stage (p < 0.04). A decline of NO levels was observed during recovery. Steroid t reatment induced a significant decrease in the PBMC NO production of M S patients during exacerbations (p < 0.01). The levels of IL-1 beta, I FN-gamma and TNF-alpha are significantly higher in the supernatants of the PBMCs which produced greater amounts of NO (p < 0.02, p < 0.03, p < 0.01, respectively). On the other hand, NO levels were negatively r elated to IL-10 and TGF-beta production (R = -75, p < 0.0001 and R = - 0.79, p < 0.0001, respectively). The increase production of NO by peri pheral blood mononuclear cells demonstrated in our study to be associa ted with increased production of proinflammatory cytokines could there fore be considered to be a marker of mononuclear cell activation in th e peripheral blood of h MS patients and, indirectly, of disease activi ty. its increased secretion during T cell and monocyte homing in the C NF could contribute to the damage to the blood-brain barrier and the s ubsequent cytokine-mediated cytotoxic effect to myelin and oligodendro cytes in the white matter of MS patients. (C) 1997 Elsevier Science B. V.