T Cell Lymphokine-Induced Secretion of Cytokines by Monocytes from Patients with Multiple Sclerosis

To investigate the function of peripheral blood monocytes in multiple sclerosis (MS), we measured the production of the cytokines interleukin-1β (IL-1β), tumor necrosis factor α (TNFα), and interleukin-6 (IL-6), and the procoagulant, tissue factor (TF) in 17 patients with chronic progressive MS and 15 normal controls. Monocyte activity was tested under unstimulated, minimal endotoxin conditions and after culture with various stimuli, including Escherichia coli lipopolysaccharide (LPS), crude supernatant from anti-CD3-activated T cells, recombinant interleukin-2 (rIL-2), and recombinant interferon-γ (rIFN-γ). A higher number of MS patients than controls had circulating monocytes which spontaneously secreted IL-6 or contained detectable cell-associated IL-1β. Monocyte responses to LPS were comparable between the two groups: LPS caused production and secretion of all cytokines and TF in every MS patient and control. In contrast crude T cell supernatants, rIL-2, and rIFN-γ induced IL-1β release in a higher number of MS monocytes than that in controls, whereas the production and secretion of the other cytokines and TF activity were similar between the groups. We conclude that some MS patients have "primed" circulating monocytes, as shown by excessive spontaneous IL-6 release and intracellular IL-1β synthesis. Unstimulated MS monocytes, however, are not different from controls with respect to spontaneous secretion of small amounts of IL-1β and TNFα and expression of cell surface TF. Excessive IL-1β secretion by MS monocytes after stimulation with T-cell-derived lymphokines suggests dys-regulation of T cell-monocyte interactions which may be most relevant in the central nervous system plaques where activated T cells are found.