Ibuprofen and other widely used non-steroidal anti-inflammatory drugs inhibit antibody production in human cells
Introduction
Non-steroidal anti-inflammatory drugs (NSAIDs) are regularly used by more than 60 million Americans [1] and are effective in relieving pain, reducing fever and inhibiting inflammation. Most NSAIDs target the activity of the prostaglandin G/H synthases, commonly known as cyclooxygenases. Cyclooxygenases (Cox-1 and Cox-2) catalyze the conversion of arachidonic acid to prostaglandin H2 (PGH2) which is metabolized by tissue-specific isomerases to other prostanoids (PGD2, PGE2, PGF2α, PGI2) and thromboxanes. Classically, Cox-1 has been described as the isoform which is constitutively expressed in most tissues and cells and plays a role in homeostasis, while Cox-2 generates PGs that act as mediators of fever, inflammation and promoters of carcinogenesis [2], [3].
There are over 50 different NSAIDs available [4] and they can be divided into different groups based on their chemical structure, pharmacokinetics and selectivity towards Cox-1 or Cox-2 [5], [6]. NSAIDs can cause liver damage [7], renal failure [8], aseptic meningitis [9] and can interfere with bone fracture healing [10]. Among the side-effects caused by NSAIDs, gastrointestinal toxicity is one of the most common [11] and results mostly from inhibition of Cox-1 in the gastric mucosa. This problem was thought to be circumvented by developing highly selective Cox-2 inhibitors (celecoxib, rofecoxib, valdecoxib), however, their use was associated with an increased incidence of myocardial infarction and stroke [12], [13]. Besides these life-threatening side-effects, there is increased evidence that NSAIDs have immunomodulatory effects by interfering with human monocyte and T lymphocyte activation, proliferation and cytokine synthesis [14], [15], [16].
The effects, if any, of Cox-1/Cox-2 non-selective over-the-counter NSAIDs on human B lymphocytes are relatively unknown. Our laboratory recently reported that inhibition of Cox-2 activity in normal human B lymphocytes by highly selective Cox-2 inhibitors (e.g., SC-58125 and NS-398) resulted in a significant decrease in antibody synthesis [17], [18]. We also showed that Cox-2 knock-out mice made less antibody than normal mice [17]. Therefore, we hypothesized that widely used Cox-1/Cox-2 non-selective NSAIDs would have a negative effect on normal B cell function. Herein, we have investigated, (1) the effect of aspirin, ibuprofen, naproxen and tylenol on antibody synthesis in human peripheral blood mononuclear cells; (2) the time-frame and the concentrations of ibuprofen required to blunt antibody synthesis and (3) the effect of ibuprofen on B cell lymphocytes. Overall, our findings reveal that over-the-counter NSAIDs have potent negative effects on human B lymphocytes and on antibody production.
Section snippets
Reagents
Aspirin (acetylsalicylic acid), ibuprofen (α-methyl-4-(isobutyl) phenylacetic acid), indomethacin (1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indoleacetic acid), S-ibuprofen (S-(+)-4-isobutyl-α-methyl-phenylacetic acid), tylenol (acetaminophen), naproxen (S)-(+)-6-methoxy-α-methyl-2-naphthaleneacetic acid) and 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) were obtained from Sigma (St. Louis, MO). SC-58125 was obtained from Cayman (Ann Arbor, MI). Stock solutions of NSAIDs
NSAIDs inhibit human antibody production in vitro
We previously reported that Cox-2 selective inhibitors blunt antibody production in vitro[17], [18]. In our current studies we tested if inhibition of antibody production was drug-specific or whether other widely used over-the-counter NSAIDs would also interfere with antibody synthesis. Human PBMCs were stimulated with anti-IgM (2 μg/ml) + CpG 2395 (1 μg/ml) for 7 days and cells were exposed to a panel of NSAIDs: ibuprofen (50 and 100 μM), aspirin (100 and 500 μM), tylenol (20 and 80 μM) and naproxen
Discussion
Because NSAIDs are one of the most commonly used class of drugs, we thought it important to investigate whether or not the over-the-counter NSAIDs would interfere with antibody synthesis. Here, we show that aspirin, ibuprofen, tylenol and naproxen (used at pharmacological concentrations) blunt antibody production in human PBMC in vitro. Low-dose aspirin (50–100 mg/day) has been shown to reduce the incidence of myocardial infarction and stroke [28], effects attributed to the irreversible
Acknowledgments
This research was supported by USPHS Grants: DE011390, ES01247, AI071064 and T-32-DE007202.
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