On the cytotoxic and proinflammatory properties of eosinophils

Abstract: Eosinophils are multi-functional leukocytes involved in the pathophysiology of inflammatory diseases such as asthma and inflammatory bowel disease. Participation in some neoplastic diseases and in the host defense against helminths has also been postulated. They are considered both good and bad, protecting or harming the host. The exact roles of eosinophils and their mechanisms of action are poorly understood. Eosinophils possess an arsenal of mediators, such as cytotoxic granule proteins, cytokines, chemokines and lipid mediators, together with the potency of producing oxygen radicals. These properties may contribute to host defense. In this thesis the cytotoxic mechanisms, using E. coli as a model system, have been investigated. The killing of E. coli was largely oxygen-dependent. Eosinophil peroxidase (EPO) together with hydrogen peroxide and a halide yield a cytotoxic product. This system proved to be efficient since blockage of EPO resulted in decreased killing. The specific granules are focus for much interest, since they are a typical feature of the cell and can as an active compartment either be degranulated out of the cell or into a phagosome. Therefore possible lysosomal characteristics were studied, leading to the conclusion that specific granules are to be considered lysosomes. Eosinophils are not only a source of cytotoxicity. They can also also have roles in the coordination of the inflammatory process in some diseases. It is here shown that eosinophils can, both in vitro and in vivo produce a chemokine that attract neutrophils, growth-related oncogene-alpha (GRO-alpha). Upon stimulation with interferon-gamma, a Th1 cytokine, eosinophils respond by down-regulating the production of GRO-alpha and instead initiate the production of the T cell attracting chemokines monokine induced by gamma-interferon (MIG), interferon-inducible protein-10 (IP-10) and Interferon-inducible T cell alpha-chemo-attractant (I-TAC). Altogether, these new findings extend the understanding of eosinophils in health and disease.