Oral aspirin and ibuprofen increase cytokine‐induced synthesis of IL‐1β and of tumour necrosis factor‐αex vivo

Abstract

SUMMARYWe investigated the effect of oral aspirin and ibuprofen on the ex vivo synthesis of interleukin-1a (IL1a), IL-1b, IL-2, IL-6, tumour necrosis factor-a (TNF) and granulocyte-macrophage colonystimulating factor (GM-CSF) by stimulated peripheral blood mononuclear cells (PBMC) from healthy volunteers. Seven volunteers took 325 mg of aspirin daily for 14 days. Three weeks after ending aspirin medication, ex vivo IL-1b and TNF synthesis induced by exogenous IL-1a was elevated threefold compared to the pre-aspirin value (P 0 . 01 and P 0 . 005, respectively). Using lipopolysaccharide (LPS) as a stimulus, no influence of oral aspirin was observed. The increase in cytokine synthesis did not parallel decreased synthesis of prostaglandin E 2 (PGE 2 ). Seven weeks after discontinuation of aspirin, cytokine and PGE-2 production returned to pre-aspirin levels. Another seven volunteers took 200 mg of ibuprofen daily for 12 days. Again, there was no effect on LPS-or Staphylococcus epidermidis-induced cytokine synthesis. However, IL-1a-induced synthesis of IL-1b was elevated to a mean individual increase of 538% (P < 0 . 001) and synthesis of TNF was elevated to 270% (P < 0 . 001) at the end of ibuprofen medication and 2 weeks after discontinuation of ibuprofen. There were parallel increases in PGE 2 and both returned to their pre-ibuprofen levels 5 weeks after stopping. Although inhibitors of cyclo-oxygenase blunt PGE 2 -mediated symptoms such as fever and pain, we conclude that short term use of either aspirin or ibuprofen results in a 'rebound' increase in cytokine-induced cytokine synthesis that is not observed in LPS-induced cytokines.

Salicylate Blocks Lipolytic Actions of Tumor Necrosis Factor-α in Primary Rat Adipocytes

“…Important discrepancies between these studies included lower salicylate dosages (Ͻ3 g/day) and therapeutic duration (a few days) in the more recent studies than in the earlier studies (6 -9 g/day for 1-3 weeks). Although salicylate reduces TNF-␣ production in rat macrophages (Vittimberga et al, 1999), administration of low-dose aspirin (325 mg/days) may result in a rebound increase in cytokine-induced synthesis of interleukin-1␤ and TNF-␣ in human (Endres et al, 1996), which can be expected to impair insulin sensitivity. Most recently, several studies indicate that high doses of salicylates attenuate deleterious effects of lipids and therefore improve lipid-induced insulin resistance both in rodents (Kim et al, 2001;Yuan et al, 2001) and humans (Hundal et al, 2002;Möhlig et al, 2006).…”

Phenotyping drug polypharmacology via eicosanoid profiling of blood

“…Interestingly, selective COX2 inhibition (NS398), but not selective COX1 inhibition (SC-560), exerted a stimulatory effect on the expression of proinfl ammatory cytokines ( 47 ). In a more translational study, Endres and coworkers ( 48 ) showed that short-term use of either aspirin or ibuprofen results in a "rebound" increase in cytokine-induced (e.g., IL-1 ␤ ) cytokine synthesis (TNF ␣ ) in humans. These results collectively support homoeostatic functions of arachidonic metabolites.…”

Effects of quercetin on exercise potential and exercise-induced cytokines in the horse

“…Cytokines behaving in an endocrine manner, such as interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), can have far-reaching effects, such as inducing generalized septic shock syndrome in species ranging from mice to humans (Beutler and Cerami, 1987;Akira et al, 1993;Dinarello, 1996). IL-1ß and TNF-α can also have biologic activity when expressed on the cell surface in membrane-bound form …”

“…IL-1 is a pleiotropic cytokine that acts on leukocytes, endothelial cells, hepatocytes, myocytes, adipose tissue, and certain neurons (Dinarello, 1996). There are two active forms of IL-1, IL-1α and IL-1ß, and typically their biological activities are indistinguishable.…”