Anti-inflammatory effect of Viscum album agglutinin-I (VAA-I): induction of apoptosis in activated neutrophils and inhibition of lipopolysaccharide-induced neutrophilic inflammation in vivo.

Viscum album agglutinin-I (VAA-I) is a plant lectin which possesses antitumoral properties. This lectin is also known for its immunostimulatory effects when used at low concentrations (1-100 ng/ml). We have demonstrated recently that VAA-I is a potent inducer of human neutrophil apoptosis in vitro when used at higher concentrations. The role of VAA-I on activated neutrophils has not so far been investigated and its potential proinflammatory properties in vivo are poorly documented. Herein, we demonstrated that VAA-I (1000 ng/ml) induces apoptosis in lipopolysaccharide (LPS)-treated human neutrophils in vitro as well as in murine neutrophils isolated from lipopolysaccharide (LPS)-induced neutrophil influx. Using this model, we found that administration of VAA-I (100 or 1000 ng/ml) did not induce an inflammatory response. However, when used at 1 or 10 ng/ml, VAA-I was found to significantly induce a transitory inflammatory response, based on an increased leucocyte infiltration (>98% neutrophils). Also, we found that VAA-I inhibits LPS-induced neutrophil influx when administered simultaneously with LPS. In such conditions, some characteristic apoptotic neutrophils were observed in the pouch. Unlike LPS, which increased the production of some cytokines, VAA-I (1 or 10 ng/ml) did not increase the production of tumour necrosis factor (TNF)-alpha, interleukin (IL)-1Ra, IL-1alpha, IL-beta, IL-8, IL-10 or IL-12 (p70) in human neutrophils. We conclude that VAA-I possesses the ability to induce apoptosis of preactivated neutrophils at a concentration that does not induce a proinflammatory response. Moreover, we conclude that VAA-I can inhibit a LPS-induced proinflammatory response in vivo. These data may provide new clinical perspectives in future mistletoe therapy and favour its potential utilization based on anti-inflammatory activity that at first appears contradictory with its use as immunostimulant.