PAI-2 inhibits the chemiluminescence of phagocytes and suppresses autoimmunity

Abstract

Abstract Activated phagocytes participate in inflammation and in the lysis of tissue or fibrin. An important inflammation mediator is singlet molecular oxygen ( 1 O 2 ), an excited oxidant that emits light when it reverts to its ground state. Other products of activated macrophages are urokinase (u-PA) and plasminogen activator inhibitor (PAI)-2. PAI-2 in physiological concentrations inhibited the hydrogen peroxide-dependent chemiluminescence (CL) of human phagocytes: 1 unit/ml (about 10 ng/ml) of PAI-2 decreased the CL of 2 × 10 5 neutrophil granulocytes to about 50%. Preincubation of PAI-2 with excess amounts of urokinase, resulting in complexed PAI-2, also decreased CL. 5 units of PAI-2 injected intraperitoneally in mice suppressed, 2 or 24 h post injection, the CL of stimulated peritoneal macrophages by 48 or 67% respectively. Rats with experimental allergic encephalomyelitis (EAE), an animal model for the human disorder multiple sclerosis (MS), were treated with PAI-2. The inhibitor was injected intraperitoneally (1) at days 0–9 or (2) at days 7–16 after EAE induction. At 17.4 ± 1.5 days after EAE induction, non-treated control rats died. In contrast, 40 out of 40 animals treated with ≥50 units of PAI-2/ animal/ day survived. Treatment with 100 units of PAI-2/ animal/day resulted in less paralytic complications, especially when PAI-2 was injected at days 7–16 after EAE induction. Women with MS have a decreased disease intensity in pregnancy. PAI-2 is elevated in blood of healthy pregnant women (about 30 units/ml PAI-2 at term). Imitation of this physiologic immunsuppression by therapeutic application of PAI-2 could be indicated in a broad range of human diseases of autoimmune character, such as MS. The present findings could have relevance for the understanding of the pathogenesis of autoimmunity.