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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)‐α, interleukin (IL)‐1Ra, IL‐1α, IL‐β, 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.