| 1. |
- Bergh Thorén, Fredrik, 1976, et al.
(författare)
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Cutting edge: Antioxidative properties of myeloid dendritic cells: protection of T cells and NK cells from oxygen radical-induced inactivation and apoptosis
- 2007
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Ingår i: J Immunol. - 0022-1767. ; 179:1, s. 21-5
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Tidskriftsartikel (refereegranskat)abstract
- Dendritic cells (DCs) communicate with nonadaptive and adaptive lymphocytes on multiple levels. Efficient DC-lymphocyte interactions require that lymphocytes remain viable and functional also under conditions of oxidative stress, such as in microbial infection or in the malignant microenvironment. For this study, we exposed human T and NK cells to oxidants delivered either by autologous phagocytes or in the form of exogenous hydrogen peroxide. In accordance with earlier studies, these lymphocytes became dysfunctional and subsequently apoptotic. The presence of myeloid DCs efficiently rescued T cells (CD4+ and CD8+) and NK cells from oxidant-induced inactivation and apoptosis. The mechanism of the myeloid DC-mediated lymphocyte protection was, at least in part, explained by the capacity of the myeloid DCs to neutralize extracellular oxygen radicals, which, in turn, was reversible upon coincubation with a catalase inhibitor. Our results are suggestive of a novel aspect of DC-lymphocyte interaction that may have implications for lymphocyte function in inflamed tissue.
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| 2. |
- Betten, Åsa, 1967, et al.
(författare)
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A proinflammatory peptide from Helicobacter pylori activates monocytes to induce lymphocyte dysfunction and apoptosis
- 2001
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Ingår i: J Clin Invest. ; 108:8, s. 1221-8
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Tidskriftsartikel (refereegranskat)abstract
- Infection with Helicobacter pylori causes chronic gastritis, which is characterized by a dense mucosal infiltration by inflammatory cells such as monocytes/macrophages. H. pylori-induced inflammation is a risk factor for the development of gastric adenocarcinoma, but the mechanisms involved in H. pylori-associated carcinogenesis are poorly understood. A cecropin-like H. pylori peptide, Hp(2-20), was found to be a monocyte chemoattractant and activated the monocyte NADPH-oxidase to produce oxygen radicals. The receptors mediating monocyte activation were identified as FPRL1 and the monocyte-specific orphan receptor FPRL2. Hp(2-20)-activated monocytes inhibited lymphocytes with antitumor properties, such as CD56+ natural killer (NK) cells and CD3epsilon+ T cells. The changes observed in NK cells and T cells--a reduced antitumor cytotoxicity, downregulation of CD3zeta expression, and apoptosis--were mediated by Hp(2-20)-induced oxygen radicals. Histamine, a gastric mucosal constituent, rescued NK cells and T cells from inhibition and apoptosis by suppressing Hp(2-20)-induced oxygen radical formation. We conclude that H. pylori expression of this monocyte-activating peptide contributes to its ability to attract and activate monocytes and reduces the function and viability of antineoplastic lymphocytes. These novel mechanisms may be subject to local, histaminergic regulation in the gastric mucosa.
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| 3. |
- Betten, Åsa, 1967, et al.
(författare)
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Histamine inhibits neutrophil NADPH oxidase activity triggered by the lipoxin A4 receptor-specific peptide agonist Trp-Lys-Tyr-Met-Val-Met
- 2003
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Ingår i: Scand J Immunol. ; 58:3, s. 321-6
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Tidskriftsartikel (refereegranskat)abstract
- The vasoactive amine histamine is found at high concentrations in the immune and inflammatory tissues. Earlier studies have revealed that histamine regulates the nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase-dependent formation of oxygen radicals by phagocytic cells. However, the effects of histamine on intracellular signal transduction mechanisms of relevance to oxidase regulation remain controversial. For this study, we investigated the effects of histamine on NADPH oxidase activity in human neutrophil granulocytes triggered by a lipoxin A4 receptor agonist [the hexapeptide Trp-Lys-Tyr-Met-Val-Met (WKYMVM), a formyl peptide receptor (FPR) agonist (the chemotactic tripeptide formylmethionyl-leucyl-phenylalanine (fMLF)) and an activator of protein kinase C (phorbol myristate acetate (PMA)]. We report that histamine, acting via H2-type histamine receptors (H2R), suppresses NADPH oxidase-dependent formation of oxygen radicals induced by WKYMVM and fMLF but not that induced by PMA. Peptide-induced mobilization of granule-localized complement receptor 3 (CR3) was unaffected by histamine suggesting that the inhibition specifically affected NADPH oxidase activation. Our data suggest that histamine downregulates FPRL1- and FPR-induced NADPH oxidase activity upstream of protein kinase C (PKC) and downstream of the separation of the peptide-induced signal into granule secretion and oxidase activation.
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| 4. |
- Betten, Åsa, 1967, et al.
(författare)
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Oxygen radical-induced natural killer cell dysfunction: role of myeloperoxidase and regulation by serotonin
- 2004
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Ingår i: J Leukoc Biol. ; 75:6, s. 1111-5
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Tidskriftsartikel (refereegranskat)abstract
- Natural killer (NK) cells are functionally suppressed and induced to apoptosis by reactive oxygen species (ROS) produced by mononuclear phagocytes (MPs). These inhibitory events are reversed by the biogenic amine serotonin. MPs generate hydrogen peroxide (H(2)O(2)), which is processed further by myeloperoxidase (MPO) to even more toxic compounds. Earlier studies suggest that serotonin scavenges MP-derived oxygen radicals generated by the MPO-H(2)O(2) system. These findings led us to explore the capability of MPO-deficient MPs to induce NK cell dysfunction. We show that MPs recovered from subjects with MPO deficiency trigger inhibition of NK cells. In addition, MPs recovered from healthy subjects conveyed suppression of NK cells in the presence of the MPO inhibitor ceruloplasmin. We conclude that ROS-dependent inhibition of NK cell function is unrestricted by the availability of MPO-derived oxygen radicals and that the protecting properties of serotonin may operate in the absence of functional MPO. Our data suggest a complex mechanism of MP-induced NK cell inhibition, which comprises the generation of interchangeable oxygen radicals.
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| 5. |
- Betten, Åsa, 1967
(författare)
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Reactive oxygen species as signalling molecules in immunity
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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.
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| 6. |
- Hansson, Markus, 1974, et al.
(författare)
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Histamine protects T cells and natural killer cells against oxidative stress.
- 1999
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Ingår i: Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research. - 1079-9907. ; 19:10, s. 1135-44
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Tidskriftsartikel (refereegranskat)abstract
- Oxidative stress inflicted by monocytes/macrophages (MO) is recognized as an important immunosuppressive mechanism in human neoplastic disease. We report that two types of lymphocytes of relevance for protection against malignant cells, T cells and natural killer (NK) cells, became anergic to the T cell and NK cell activator interleukin-2 (IL-2) after exposure to MO-derived reactive oxygen metabolites and subsequently acquired features characteristic of apoptosis. The MO-induced anergy and apoptosis in T cells and NK cells were reversed by histamine, an inhibitor of reactive oxygen metabolite synthesis in MO. We propose that strategies to circumvent oxidative inhibition of lymphocytes may be of benefit in immunotherapy of neoplastic disease.
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