In order to examine the plasminogen activator (PA) induction involved in the pathogenesis of acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS), PA activity in peripheral blood lymphocytes derived from 5 ADEM and 3 MS patients was investigated. There was no PA induction in any ADEM, MS or control lymphocytes treated with N-methyl-N’-nitro-N-nitro-soguanidine (MNNG) alone. PA activity, however, in lymphocytes exposed to human interferon-y (HulFN-y) prior to MNNG treatment was elevated during the active phase of ADEM and MS, whereas the PA induction disappeared in association with improvement of the neurologic symptoms. The PA activity was abolished by mixed treatment with HuIFN-y and anti-HulFN-y antibody. No such PA induction by any HulFN was observed in any normal controls or cases of other neurologic diseases. Among the cytokines tested other than HulFN, tumor necrosis factor-a, in combination with MNNG, also induced PA activity in lymphocytes from ADEM and MS patients during the active phase. Thus, the PA induction observed in lymphocytes on combined treatment with MNNG and cytokines may be involved in the progression of neurologic disorders in these demyelinating diseases, and indicates the possibility of therapeutic strategies involving anticytokine usag