Aspirin and thymosin increase interleukin-2 and interferon-γ production by human peripheral blood lymphocytes

Hsia, Judith; Sarin, Neil; Oliver, Janelle; Goldstein, Allan L.

doi:10.1016/0162-3109(89)90045-3

Cited by 39 publications

(27 citation statements)

References 20 publications

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“…Support to this view comes from the following observations: first, exposure of resting lymphocytes (and monocytes) to NCX-4016 leads to NO formation; second, NCX-4017, a non-NO-releasing analog of NCX-4016, ASA, and selective and nonselective COX-2 inhibitors reduce prostanoid generation, but fail to inhibit cytokine release induced by anti-CD3/anti-CD28 and LPS (27). In contrast, we observed a slight, although significant increase of IL-1␤ and TNF-␣ release from monocytes incubated with ASA, suggesting that endogenous prostanoid contributes to limit cytokine/chemokine release in immune cells (30,31); third, inhibition of cytokine release and mitochondrial perturbation caused by NCX-4016 was, at least partially, reproduced by incubating lymphocytes and monocytes with the NO donor DETA-NO; and, finally, scavenging NO with Hb greatly attenuated inhibition of cytokine secretion and mitochondrial effects of NCX-4016 and DETA-NO.…”

Section: Discussioncontrasting

confidence: 50%

Nitric Oxide Regulates Immune Cell Bioenergetic: A Mechanism to Understand Immunomodulatory Functions of Nitric Oxide-Releasing Anti-Inflammatory Drugs

Fiorucci

Mencarelli

Distrutti

et al. 2004

The Journal of Immunology

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The 2-(acetyloxy)benzoic acid 3-(nitrooxymethyl)phenyl ester (NCX-4016) is a NO-releasing derivative of aspirin. In this study, we provide evidence that NCX-4016 delivered to PMBC-derived T lymphocytes and monocytes causes a transitory inhibition of cell respiration and ≈50% reduction of cellular ATP, which translates in a time-reversible inhibition of cell proliferation and IL-2, IL-4, IL-5, and IFN-γ secretion. Exposure of lymphocytes and monocytes to aspirin, 2-(acetyloxy)benzoic acid 3-(hydroxymethyl)phenyl ester (NCX-4017), a non-NO-releasing analog of NCX-4016, and cyclooxygenase inhibitors, reduced PG formation, but has no effect on cytokine/chemokine release. In contrast, delivering NO with (z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino] diazen-1-ium-1,2 diolate (DETA-NO) reproduced most of the metabolic and anti-cytokine activities of NCX-4016. Scavenging NO with hemoglobin or adding selective substrates of complex II, III, and IV of the mitochondrial respiratory chain reverses NCX-4016′ inhibitory activities. Exposure to DETA-NO and NCX-4016 enhances glucose uptake, glycolytic rate, and lactate generation in CD3/CD28-costimulated lymphocytes, while reduced citric acid cycle intermediates. These effects were not reproduced by selective and nonselective cyclooxygenase 2 inhibitors. In summary, we demonstrated that exposure of lymphocytes to NCX-4016 causes a metabolic hypoxia that inhibits lymphocyte reactivity to costimulatory molecules, providing a potential counteregulatory mechanism to control activated immune system.

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Section: Discussioncontrasting

confidence: 50%

Nitric Oxide Regulates Immune Cell Bioenergetic: A Mechanism to Understand Immunomodulatory Functions of Nitric Oxide-Releasing Anti-Inflammatory Drugs

Fiorucci

Mencarelli

Distrutti

et al. 2004

The Journal of Immunology

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“…In vitro, treatment of T lymphocytes with PG inhibits their activation and proliferation [9±11]. Conversely, treatment with such PG synthesis inhibitors as non-steroidal antiin¯ammatory drugs (NSAID) increase proliferation and activation of T cells [12,13]. Data regarding the ability of T cells to synthesize PG from AA precursors are contradictory.…”

Section: Introductionmentioning

confidence: 99%

Cyclooxygenase-1 and -2 are expressed by human T cells

Pablos¹,

Santiago²,

Carreira³

et al. 1999

Clinical and Experimental Immunology

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SUMMARYIn vitro, prostaglandins (PG) have strong inhibitory effects on T cell activation and proliferation and inhibitors of PG synthesis (NSAID) increase proliferation and activation of T cells. Although most studies have failed to demonstrate cyclooxygenase (COX) activity in lymphocytes, there is contradictory evidence on the synthesis of different PG. We have studied by reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot the expression of COX-1 and -2 mRNA and protein in resting and activated peripheral blood or Jurkat T cells. Cells were activated by T cell receptor triggering with OKT3 antibodies and activation con®rmed by¯ow cytometric analysis of surface CD69. COX enzymatic activity was measured by determination of arachidonic acid (AA)-induced PG synthesis. Both peripheral blood and Jurkat T cells expressed COX-1 and -2 mRNA and protein. COX-1 was constitutively expressed and did not change after OKT3 stimulation. COX-2 was inducible upon OKT3-induced activation. In spite of the presence of COX mRNA and immunoreactive protein, AA-induced PG synthesis was not detected at the EIA detection (pM) level. The potential role of cyclooxygenases in T cells deserves further study, since no PG of the studied series seem to be synthesized by T cells.

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“…Decreased production of immunomodulating PGs, such as prostaglandin E 2 (PGE 2 ), in accessory cells may account for the ability of ASA and other NSAIDs to bolster T helper (Th)1-driven cellular immune responses. 19,20 ASA and ibuprofen can enhance mitogen-induced T-cell proliferation and the expression of interleukin-2 (IL-2), IFN-␥, 21,22 macrophage-derived IL-1␤, tumor necrosis factor-␣, and IFN-␣. 23,24 Conversely, by inhibiting NF-B and perhaps other mechanisms, high concentrations of salicylates interfere with Th1-cell differentiation and effector responses.…”

Section: Introductionmentioning

confidence: 99%

Selective inhibition of interleukin-4 gene expression in human T cells by aspirin

Cianferoni¹,

Schroeder²,

Kim³

et al. 2001

Blood

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IntroductionAspirin (acetylsalicylic acid [ASA]) is the oldest and most widely used nonsteroidal anti-inflammatory drug (NSAID). Although several other classes of NSAIDs have become available since the introduction of ASA in 1899, this agent and structurally related salicylates still provide the mainstay of therapy for inflammatory musculoskeletal disorders. In addition, these compounds have been shown to be effective in the management and prevention of an increasingly diverse array of noninflammatory conditions, including coronary and cerebral ischemia and gastrointestinal cancer. 1,2 Both the therapeutic properties of NSAIDs and their side effects have been ascribed to their ability to inhibit generation of prostaglandin (PG) and thromboxane by interfering with the intracellular enzyme cyclo-oxygenase (COX). 3 It is widely accepted that the anti-inflammatory actions of NSAIDs are mediated by inhibition of the inducible COX isoform COX-2, whereas their detrimental effects on gastric mucosa viability and platelet function are due mostly to inhibition of COX-1. 4 The relative effectiveness of several NSAIDs against the 2 isozymes varies considerably. 5 In particular, although ASA is a relatively effective, irreversible inhibitor of COX-1, its effects on COX-2 activity are negligible. 5 This probably explains why higher doses of ASA are required in the treatment of chronic inflammatory diseases than are sufficient to inhibit PG generation in different experimental models in vitro. 6 However, the in vivo anti-inflammatory and anticancer activity of nonacetylated salicylates, which are poor overall inhibitors of both COX-1 and COX-2, is almost superimposable to that of ASA or even more potent NSAIDs, such as diclofenac. 7 Indeed, given the short serum half-life of ASA (15 minutes), the serum concentrations of salicylic acid (SA), its major nonacetylated metabolite, are better predictors of therapeutic effectiveness than the concentrations of ASA itself. 6 In the light of these observations, it has been speculated that inhibition of PG production cannot fully account for the therapeutic potential of ASA and related salicylates. 6 Indeed, several studies showed that these compounds have a spectrum of biochemical and pharmacologic effects that are not related to COX inhibition and not shared with other NSAIDs. [8][9][10][11][12][13][14][15] A major finding was the discovery that ASA and SA can interfere with the activation of critical transcription factors, such as nuclear factor (NF) B (NF-B) and activator protein 1 (AP-1). 8,10 On the other hand, salicylates were reported to activate mitogen-activated protein kinases and enhance interferon (IFN) signaling. 13,16,17 These overall effects of salicylates are compounded by their ability to induce the release of potent anti-inflammatory mediators, such as adenosine and 15-epi-lipoxin A 4 . 9,14 Taken together, these observations support the idea that the multiple therapeutic effects of ASA derive from its ability to regulate a network of biochemical and cellular events mo...

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Aspirin and thymosin increase interleukin-2 and interferon-γ production by human peripheral blood lymphocytes

Cited by 39 publications

References 20 publications

Nitric Oxide Regulates Immune Cell Bioenergetic: A Mechanism to Understand Immunomodulatory Functions of Nitric Oxide-Releasing Anti-Inflammatory Drugs

Nitric Oxide Regulates Immune Cell Bioenergetic: A Mechanism to Understand Immunomodulatory Functions of Nitric Oxide-Releasing Anti-Inflammatory Drugs

Cyclooxygenase-1 and -2 are expressed by human T cells

Selective inhibition of interleukin-4 gene expression in human T cells by aspirin

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