Reactive oxygen species as signalling molecules in immunity

Abstract: Cytotoxic lymphocytes such as natural killer (NK) cells and subsets of T cells are key components of the host defense against malignancy and infection. Earlier studies have demonstrated that NK cells and several phenotypes of T cells become dysfunctional and apoptotic after exposure to autologous monocyte/macrophages and other phagocytes. Reactive oxygen species (ROS, "oxygen radicals"), which are produced by phagocytes, have been shown to mediate the NK and T cell inhibition. This thesis has focused on the mechanisms of lymphocyte inhibition by phagocyte-derived ROS, along with studies of the mechanisms underlying lymphocyte-protective properties of two biogenic amines, serotonin and histamine.Serotonin was found to efficiently protect NK cells against functional inhibition and apoptosis induced by phagocyte-derived ROS. The effect was explained by the unexpected capacity of serotonin to scavenge ROS. The scavenging activity was specific in that serotonin scavenged peroxidated derivatives of hydrogen peroxide, but not hydrogen peroxide alone. In addition, it was found that phagocyte-induced inhibition of lymphocytes was not restricted by the availability of myeloperoxidase, which is a main source of peroxidase in phagocytes. These results may be suggestive of a role for serotonin in protecting adjacent cells, including cytotoxic lymphocytes, against ROS-inflicted damage at sites of inflammation.Histamine protected NK cells and other lymphocytes against phagocyte-induced inhibition and apoptosis as efficiently as serotonin, but with an entirely different mechanism of action. Thus, histamine interacted with H2-type histamine receptors on phagocytes to target the NADPH oxidase, a key starting enzyme in ROS production. Thereby, histamine suppressed ROS formation in response to several ROS-inducing stimuli, including a peptide [Hp(2-20)] encoded by Helicobacter pylori. Hp(2-20) triggered a pronounced ROS formation in phagocytes by interacting with FPRL1 and FPRL2 receptors, and also induced secondary functional inhibition and apoptosis in cytotoxic lymphocytes. By reducing the Hp(2-20)-induced ROS production, histamine protected NK cells and T cell subsets against inhibition and apoptosis. It is hypothesized that the immunosuppressive and ROS-inducing properties of Hp(2-20) may be of relevance to cancer development in H. pylori-infected gastric tissue, and that histamine, which is found at high concentrations in gastric mucosa, may have a role in maintaining the function and viability of cytotoxic lymphocytes in H. pylori-infected tissue.