Inhibition of Human NK Cell Cytotoxicity by Induction of Cyclic AMP Depends on Impaired Target Cell Recognition

Ullberg, Måns; Jondal, Mikael; Lanefelt, Fred; Fredholm, Bertil B.

doi:10.1111/j.1365-3083.1983.tb00801.x

Cited by 38 publications

(18 citation statements)

References 39 publications

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“…Both spontaneous cytotoxicity against K562 target cells and Ab-redirected cytotoxicity triggered by activation of CD16 or NKp46 are mediated by release of cytolytic granules, a process that includes conjugation of NK and target cells, polarization of granules inside NK cells, and release of the granules at the NK-target cell interface (41,42). Studies have suggested that elevation of intracellular cAMP in NK cells inhibits their binding to target cells (43). Consistent with these reports, our present findings show that PGD 2 binding to DP enhances cAMP levels in NK cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin D2 Suppresses Human NK Cell Function via Signaling through D Prostanoid Receptor

Chen

Perussia

Campbell

2007

The Journal of Immunology

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NK cells play critical roles in immune responses against tumors or virus infections by generating type 1 cytokine and cytotoxicity responses. In contrast, during type 2 dominant immune responses, such as allergic diseases, activities of NK cells are often impaired. These type 2 immune-mediated diseases have been reported to be closely associated with local production of PGD2. PGD2 is an eicosanoid primarily synthesized by mast cells and alveolar macrophages, and it functions through two major receptors, D prostanoid receptor (DP) and chemoattractant receptor-like molecule on the Th2 cell. Within the immune system, PGD2 binding to DP generally leads to suppression of cellular functions. In the current study, we show that: 1) DP is expressed in human NK cells as detected by mRNA analysis and Western blot; 2) PGD2 inhibits cytotoxicity, chemotaxis, and type 1 cytokine production of human NK cells via signaling through DP; 3) PGD2 signaling via DP elevates intracellular cAMP levels and the inhibitory effects on NK cells are cAMP dependent; 4) PGD2 binding to DP suppresses Ca2+ mobilization triggered by the cross-linking of the activating receptor, CD16. Together, these data uncover a novel mechanism by which PGD2 functions through DP to suppress type 1 and cytolytic functions of human NK cells, thus contributing to the promotion of a type 2 immune response.

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Section: Discussionmentioning

confidence: 99%

Prostaglandin D2 Suppresses Human NK Cell Function via Signaling through D Prostanoid Receptor

Chen

Perussia

Campbell

2007

The Journal of Immunology

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“…prostaglandin E2, P-adrenoceptor agonists, forskolin) negatively influence NK cell activity (Katz et al, 1982;Goto et al, 1983;Ullberg et al, 1983;Steele & Brahmi, 1988;Windebank et al, 1988;Whalen & Bankhurst, 1990). Indeed, the percentage of NKtarget conjugates is reduced after induction of cyclic AMP (Ullberg et al, 1983;Whalen & Bankhurst, 1990), although conflicting reports exist (Katz et al, 1982;Steele & Brahmi, 1988). These results suggest that an increase in the cellular cyclic AMP content interferes with adhesion and adhesionstrengthening activation signals and our observations are compatible with these data.…”

Section: Discussionmentioning

confidence: 99%

The effects of β‐adrenoceptor stimulation on adhesion of human natural killer cells to cultured endothelium

Benschop¹,

Nijkamp

Ballieux

et al. 1994

British J Pharmacology

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1 The circulation of natural killer (NK) 3 Cells were pretreated (15 min) with a selective P2-adrenoceptor antagonist, GR81706, at various concentrations. The duration of P-adrenoceptor blockade was tested by determining the adenosine 3',5'-cyclic monophosphate (cyclic AMP) production induced by terbutaline (a P2-adrenoceptor specific agonist). This receptor-mediated response was effectively inhibited for at least 4 h, whereas the cyclic AMP production in response to forskolin (a direct activator of adenylate-cyclase) was not affected. 4 Functional adhesion assays were then performed to determine the role of P-adrenoceptors on the different cell types involved (NK and EC) in catecholamine-induced detachment. Peripheral blood mononuclear cells were allowed to adhere for 1 h to monolayers of unstimulated EC in the presence or absence of cyclic AMP inducing agents, and the percentage of NK cells in the adhering lymphocyte fraction was determined by flow cytometry. 5 Both adrenaline (10-5 M) and forskolin (10-5 M) caused detachment of NK cells from EC. After blockade of the P2-adrenoceptors on NK cells by pretreatment with GR81706 (10-6 M), the effect of adrenaline on NK cells adhesion was pretented; after blockade of the P2-adrenoceptors on EC, NK cell adhesion was still significantly reduced by adrenaline. In all cases, forskolin caused detachment of NK cells.6 To establish further that stimulation of P-adrenoceptors on NK cells is sufficient to cause detachment, we showed that adrenaline also reduced adhesion of NK cells to monolayers of Chinese hamster ovary cells, which do not express P-adrenoceptors. 7 Together, these results show that stimulation of P2-adrenoceptors on NK cells negatively influences their capacity to adhere to EC, and that P2-adrenoceptors on EC play a negligible role in this phenomenon.

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“…Tlymphocytes were isolated as previously described (Ullberg et al, 1983). In short, the fractionated cells were washed once in PBS, and the cellular pellet was resuspended in complete minimal essential medium (MEM) (MEM, supplemented with 10% heat inactivated AB + serum, 2 mM glutamine, 50 mg/ml of streptomycin and 50 mg/ml of penicillin), and incubated for 1 h on plastic dishes for depletion of adherent cells.…”

Section: T-lymphocyte Isolation and Cell Culturementioning

confidence: 99%

Involvement of the Ink4 proteins p16 and p15 in T-lymphocyte senescence

Erickson¹,

Sangfelt²,

Heyman³

et al. 1998

Oncogene

104

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Little is known about the molecular background to senescence in T-lymphocytes. In ®broblast systems replicative senescence has been shown to correlate with a number of changes in the expression of the proteins normally regulating progression through the G1 phase of the cell cycle, and recently the Ink4 inhibitor p16 was implicated as a central regulator of replicative senescence in human ®broblasts. It has, however, been claimed that p16 is not expressed in T-lymphocytes. In the present study we have analysed G1 regulating proteins in ageing human T-lymphocytes. We show that PHA and IL-2 stimulated T-lymphocytes cease to proliferate after around 20 population doublings, these cells can not thereafter be restimulated to growth, and were also found to exhibit markers for senescence. We found that Tlymphocytes accumulate p16 and p15 protein during successive population doublings and display high levels of these proteins as they enter into replicative senescence. There was also an increased binding of p16 to the Cdk6 kinase in senescent cells, and a decreased Cdk6 as well as Cdk2 kinase activity. The levels of other G1 regulating proteins were also altered in the senescent cells, such as slightly elevated levels of p21/WAF1, and downregulation of Cdk2 and cyclinD3. The levels of p27/ Kip1 is down regulated in proliferating cells but rise to approximately 15% of the levels in un-stimulated quiescent cells. As a high proportion of T-cell childhood acute lymphoblastic leukaemias have deletions of both p15 and p16, our data suggest that inactivation of these genes makes it possible for leukemic cells to avoid senescence.

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Inhibition of Human NK Cell Cytotoxicity by Induction of Cyclic AMP Depends on Impaired Target Cell Recognition

Cited by 38 publications

References 39 publications

Prostaglandin D2 Suppresses Human NK Cell Function via Signaling through D Prostanoid Receptor

Prostaglandin D2 Suppresses Human NK Cell Function via Signaling through D Prostanoid Receptor

The effects of β‐adrenoceptor stimulation on adhesion of human natural killer cells to cultured endothelium

Involvement of the Ink4 proteins p16 and p15 in T-lymphocyte senescence

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