PAI-2 inhibits the chemiluminescence of phagocytes and suppresses autoimmunity

Abstract

Activated phagocytes participate in inflammation and in the lysis of tissue or fibrin. An important inflammation mediator is singlet molecular oxygen (¹O₂), 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 × 10⁵neutrophil 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.