A Proinflammatory Peptide from Herpes Simplex Virus Type 2 Glycoprotein G Affects Neutrophil, Monocyte, and NK Cell Functions

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.

Section: Resultsmentioning

confidence: 99%

Cutting Edge: Antioxidative Properties of Myeloid Dendritic Cells: Protection of T Cells and NK Cells from Oxygen Radical-Induced Inactivation and Apoptosis

Thorén

Betten

Romero

et al. 2007

“…FPRL1 is also a selective receptor for the lipid mediator lipoxin A4 and has been also named ALX (11,12). Recently, a panoply of additional unrelated peptide agonists have been identified for FPR and FPRL1, including synthetic peptides, pathogen-derived peptides, and various host proteins and peptides (7,(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Only two naturally occurring peptide agonists have been identified to date for FPRL2: F2L and the neuropeptide humanin, both of which also activate FPRL1 (1,23).…”

Section: F Ormylpeptide Receptor (Fpr)mentioning

confidence: 99%

F2L, a Peptide Derived from Heme-Binding Protein, Chemoattracts Mouse Neutrophils by Specifically Activating Fpr2, the Low-Affinity N-Formylpeptide Receptor

Gao

Guillabert

et al. 2007

F2L (formylpeptide receptor (FPR)-like (FPRL)-2 ligand), a highly conserved acetylated peptide derived from the amino-terminal cleavage of heme-binding protein, is a potent chemoattractant for human monocytes and dendritic cells, and inhibits LPS-induced human dendritic cell maturation. We recently reported that F2L is able to activate the human receptors FPRL-1 and FPRL2, two members of the FPR family, with highest selectivity and affinity for FPRL2. To facilitate delineation of mechanisms of F2L action in vivo, we have now attempted to define its mouse receptors. This is complicated by the nonequivalence of the human and mouse FPR gene families (three vs at least eight members, respectively). When cell lines were transfected with plasmids encoding the eight mouse receptors, only the one expressing the receptor Fpr2 responded to F2L (EC50 ∼400 nM for both human and mouse F2L in both calcium flux and cAMP inhibition assays). This value is similar to F2L potency at human FPRL1. Consistent with this, mouse neutrophils, which like macrophages and dendritic cells express Fpr2, responded to human and mouse F2L in both calcium flux and chemotaxis assays with EC50 values similar to those found for Fpr2-expressing cell lines (∼500 nM). Moreover, neutrophils from mice genetically deficient in Fpr2 failed to respond to F2L. Thus, Fpr2 is a mouse receptor for F2L, and can be targeted for the study of F2L action in mouse models.

“…A cytotoxicity assay using PKH-26-labeled K562 cells was used for studying NK cell cytotoxic function (21,22). NK cells pretreated with PJ34 (500 M) or medium were exposed to mononuclear phagocytes (phagocyte:NK ratio, 1:2) or hydrogen peroxide (60 M) overnight.…”

Section: Nk Cell Cytotoxicity Assaymentioning

confidence: 99%

Oxygen Radicals Induce Poly(ADP-Ribose) Polymerase-Dependent Cell Death in Cytotoxic Lymphocytes

Thorén

Romero

Hellstrand

2006

Cytotoxic T cells and NK cells will acquire features of apoptosis when exposed to oxygen radicals, but the molecular mechanisms underlying this phenomenon are incompletely understood. We have investigated the role of two enzyme systems responsible for execution of cell death, caspases and the poly(ADP-ribose) polymerase (PARP). We report that although human cytotoxic lymphocytes were only marginally protected by caspase inhibitors, PARP inhibitors completely protected lymphocytes from radical-induced apoptosis and restored their cytotoxic function. The radical-induced, PARP-dependent cell death was accompanied by nuclear accumulation of apoptosis-inducing factor and a characteristic pattern of large-fragment DNA degradation. It is concluded that the PARP/apoptosis-inducing factor axis is critically involved in oxygen radical-induced apoptosis in cytotoxic lymphocytes.