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

Abstract

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...

Response to ‘Non‐Hodgkin's lymphoma and nonsteroidal anti‐inflammatory drugs: A confounding problem’ by Harris

“…7 cyclooxygenase (COX)-independent mechanisms may also be important. 8,9 In conclusion, there is currently no consensus with respect to the role of NSAIDs in the etiology of NHL, and we concur with Harris that future studies should be designed to carefully assess this association, including the role of confounding.…”

The Beneficial Biological Properties of Salicylic Acid

“…Stimulation of cells by LPS in the presence of SA resulted in the lack of LPS-induced proteolysis of IκB, which proved that the observed inhibition of NF-κB is mediated by inhibition of phosphorylation and/or proteolysis of IκB (24). The serum concentrations of SA between 1 and 2 mM are necessary for anti-inflammatory effects, while concentrations higher than 6 mM are toxic (28).…”

Transcriptional Control of COX-2 via C/EBPβ

“…35 We have recently shown that salicylate (10 Ϫ5 M) inhibited COX-2 and inducible nitric oxide synthase (iNOS) expression in murine RAW 264.7 cells stimulated with LPS/interferon-␥ for 4 hours by inhibiting C/EBP␤ binding but not NF-B binding. 62 Besides inhibiting COX-2 and iNOS expression, salicylate at therapeutic concentrations has been shown to inhibit IL-4 63 and IL-6 expressions (unpublished data). Because the expressions of both cytokines require C/EBP␤, it is likely that aspirin and sodium salicylate inhibit their expressions by suppressing C/EBP␤ binding.…”