It has been recently demonstrated that interleukin-1β (IL-1β) plays a central role in monosodium urate (MSU) crystal-induced inflammation and that the NALP3 inflammasome plays a major role in IL-1β production. These discoveries have offered new insights into the pathogenesis of acute gouty arthritis. In this review, we discuss the molecular mechanisms by which MSU crystals induce acute inflammation and examine the mechanisms of action (MOAs) of traditional anti-inflammatory drugs (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], colchicine, and glucocorticoids) and biologic agents (eg, the IL-1β antagonists anakinra, rilonacept, and canakinumab) to understand how their MOAs contribute to their safety profiles. Traditional anti-inflammatory agents may act on the IL-1β pathway at some level; however, their MOAs are broad-ranging, unspecific, and biologically complex. This lack of specificity may explain the range of systemic side effects associated with them. The therapeutic margins of NSAIDs, colchicine, and glucocorticoids are particularly low in elderly patients and in patients with cardiovascular, metabolic, or renal comorbidities that are frequently associated with gouty arthritis. In contrast, the IL-1β antagonists act on very specific targets of inflammation, which may decrease the potential for systemic side effects, although infrequent but serious adverse events (including infection and administration reactions) have been reported. Because these IL-1β antagonists target an early event immediately downstream from NALP3 inflammasome activation, they may provide effective alternatives to traditional agents with minimal systemic side effects. Results of ongoing trials of IL-1β antagonists will likely provide clarification of their potential role in the management of acute gouty arthritis.
interleukin-1β; anakinra; canakinumab; rilonacept; inflammation; gouty arthritis; mechanism of action; safety; biologic agents
Macrophages rely on reverse cholesterol transport mechanisms to rid themselves of excess cholesterol. By reducing accumulation of cholesterol in the artery wall, reverse cholesterol transport slows or prevents development of atherosclerosis. In stable macrophages, efflux mechanisms balance influx mechanisms and accumulating lipids do not overwhelm the cell. Under atherogenic conditions, inflow of cholesterol exceeds outflow and the cell is ultimately transformed into a foam cell, the prototypical cell in the atherosclerotic plaque. Adenosine is an endogenous purine nucleoside released from metabolically active cells by facilitated diffusion and generated extracellularly from adenine nucleotides. Under stress conditions, such as hypoxia, a depressed cellular energy state leads to an acute increase in the extracellular concentration of adenosine. Extracellular adenosine interacts with one or more of a family of G protein coupled receptors (A1, A2A, A2B and A3) to modulate the function of nearly all cells and tissues. Modulation of adenosine signaling participates in regulation of reverse cholesterol transport. Of particular note for the development of atherosclerosis, activation of A2A receptors dramatically inhibits inflammation and protects against tissue injury. Potent anti-atherosclerotic effects ofA2A receptor stimulation include inhibition of macrophage foam celltransformation and upregulation of the reverse cholesterol transport proteins cholesterol 27-hydroxylase and ATP binding cassette transporter (ABC) A1. Thus, A2A receptor agonists may correct or prevent the adverse effects of inflammatory processes on cellular cholesterol homeostasis. This review focuses on the importance of extracellular adenosine acting at specific receptors as a regulatory mechanism to control the formation of foam cells under conditions of lipid loading.
Bone is a dynamic organ that undergoes continuous remodeling whilst maintaining a balance
between bone formation and resorption. Osteoblasts, which synthesize and mineralize new bone, and
osteoclasts, the cells that resorb bone, act in concert to maintain bone homeostasis. In recent
years, there has been increasing appreciation of purinergic regulation of bone metabolism.
Adenosine, released locally, mediates its physiologic and pharmacologic actions via interactions
with G-protein coupled receptors and recent work has indicated that these receptors are involved in
the regulation of osteoclast differentiation and function, as well as osteoblast differentiation and
bone formation. Moreover, adenosine receptors also regulate chondrocyte and cartilage homeostasis.
These recent findings underscore the potential therapeutic importance of adenosine receptors in
regulating bone physiology and pathology.
Adenosine; adenosine receptors; bone resorption; bone formation; chondrocytes
Falls and resulting fractures are a leading cause of morbidity/mortality in the elderly. With the withdrawal of certain selective COX2 inhibitors in 2004, narcotic analgesics have increasingly been recommended as first-line therapy in guidelines for the treatment of chronic pain.
To evaluate the changes in types of medications prescribed for pain pre- and post-withdrawal of certain selective COX2 inhibitors in 2004 and to determine if there was an association with fall events among elderly patients with a diagnosis of osteoarthritis.
A nested case-control design using electronic medical records compiled between 2001–2009.
Electronic medical records for care provided in an integrated health system in rural Pennsylvania over a nine year period (2001–9), the midpoint of which rofecoxib (Vioxx) and valdecoxib (Bextra) were pulled from the market.
13,354 patients, aged 65–89, with a diagnosis of osteoarthritis (OA).
The incidence of falls/fractures was examined in relation to analgesics prescribed: narcotics, COX2 inhibitors, or nonsteroidal anti-inflammatory drugs (NSAIDs). The comparison sample of no fall patients was matched 3:1 to fall patients according to age, gender and comorbidity.
Narcotic analgesic prescriptions were associated with a significantly increased risk of falls/fractures. The odds ratio of experiencing a fall/fracture was higher in patients prescribed narcotic analgesics than those prescribed a COX2 inhibitor (3.3, 2.5–4.3) or NSAID (4.1, 3.7–4.5).
The increased use of narcotic analgesics is associated with an increased risk of falls/fractures in elderly patients with osteoarthritis, an observation that suggests the current guidelines for the treatment of pain, which include first-line prescription of narcotics, should be re-evaluated.
aging; osteoarthritis; pain; health care
Morning stiffness and increased symptoms of inflammatory arthritis are among the most common manifestations of rheumatoid arthritis (RA). Tumor necrosis alpha (TNF-α), an important mediator of inflammation in RA, regulates the circadian expression of clock proteins, and adenosine A2A receptors (A2AR) mediate many of the anti-inflammatory and antirheumatic actions of methotrexate, the cornerstone drug in the treatment of RA. We found that A2AR activation and TNF-α activated the clock core loop of the human monocytic THP-1 cell line. We further observed that interleukin (IL)-10, but not IL-12, mRNA expression fluctuates in a circadian fashion and that TNF-α and A2AR stimulation combined increased IL-10 expression. Interestingly, TNF-α, but not CGS21680, dramatically inhibited IL-12 mRNA expression. The demonstration that A2AR and TNF-α regulate the intrinsic circadian clock in immune cells provides an explanation for both the pathologic changes in circadian rhythms in RA and for the adverse circadian effects of methotrexate, such as fatigue.
adenosine A2 receptor; TNF-α; IL10; IL-12; clock genes; methotrexate
Accelerated osteoclastic bone resorption plays a central role in the pathogenesis of osteoporosis and other bone diseases. Because identifying the molecular pathways that regulate osteoclast activity provides a key to understanding the causes of these diseases and to the development of new treatments we studied the effect of adenosine A1 receptor blockade or deletion on bone density.
Bone mineral density (BMD) in adenosine A1 receptor knockout mice was analyzed by DEXA scan and the trabecular and cortical bone volume was determined by Micro CT. Mice were ovariectomized or sham-operated, and 5 weeks after surgery, when osteopenia had developed, several parameters were analysed by DEXA scan and MicroCT. Histological examination of bones from A1 knockout and wild type mice was carried out. Visualization of osteoblast function (bone formation) after Tetracycline double labeling was performed by fluorescence microscopy.
MicroCT analysis of bones from A1KO mice showed significantly increased bone volume. Electron microscopy of bones from A1KO mice shows an absence of ruffled borders of osteoclasts and osteoclast bone resorption. Immunohistology demonstrates that although osteoclasts are present in the A1KO mice they are smaller and often not associated with bone. No morphologic changes in osteoblasts were observed and bone labeling studies reveal no change in bone formation rates in the A1KO mice.
These results suggest that the adenosine A1 receptor may be a useful target in treating diseases characterized by excessive bone turnover such as osteoporosis and prosthetic joint loosening.
Background and purpose
Adenosine, an endogenous purine nucleoside, is a potent regulator of the inflammatory response and stimulus for fibrosis. We have previously demonstrated that adenosine, acting at the A2A receptor, plays a central role in hepatic fibrosis via direct promotion of collagen production by hepatic stellate cells. As we have previously demonstrated that macrophage A2A receptor function is regulated by interferon-gamma (IFNγ), a noted antifibrotic but pro-inflammatory cytokine, we examined its effect on A2AR-stimulated collagen production in the human hepatic stellate cell line LX-2.
Collagen expression was determined by western blotting and realtime reverse transcription polymerase chain reaction (RT-PCR). Receptor desensitization was assessed by western blotting for membrane associated GRK2. Receptor signaling was determined by western blotting for phosphorylated extracellular signal-related protein kinase (ERK) protein and immunoassay for intracellular cyclic AMP (cAMP). siRNA was used to knock down expression of adenylyl cyclase and signal transducer and activator of transcription (STAT). Adenylyl cyclase expression was assessed by realtime RT-PCR, and STAT expression was assessed by western blotting.
IFNγ diminishes A2A receptor-mediated collagen production at both protein and mRNA levels. IFNγ alters signal transduction at A2A receptors by a STAT1 mediated mechanism involving the suppression of adenylyl cyclase expression.
Conclusions and implications
IFNγ inhibits the function of the adenosine A2A receptor in hepatic stellate cells by downregulating the expression of adenylyl cyclase. This finding explains, at least in part, the protective effect of IFNγ in hepatic fibrosis.
hepatic fibrosis; collagen-1; interferon-gamma; inflammation; adenylyl cyclase; siRNA; hepatic stellate cells
Adenosine is a potent endogenous anti-inflammatory and immunosuppressive metabolite that is a potent modulator of tissue repair. However, the adenosine A2A receptor (A2AR)-mediated promotion of collagen synthesis is detrimental in settings such as scarring and scleroderma. The signaling cascade from A2AR stimulation to increased collagen production is complex and obscure, not least because cAMP and its downstream molecules PKA and Epac1 have been reported to inhibit collagen production. We therefore examined A2AR-stimulated signaling for collagen production by normal human dermal fibroblasts (NHDF). Collagen1 (Col1) and collagen3 (Col3) content after A2AR activation by CGS21680 was studied by western blotting. Contribution of PKA and Epac was analyzed by the PKA inhibitor PKI and by knockdowns of the PKA-Cα, -Cβ, -Cγ, Epac1, and Epac2. CGS21680 stimulates Col1 expression at significantly lower concentrations than those required to stimulate Col3 expression. A2AR stimulates Col1 expression by a PKA-dependent mechanism since PKA inhibition or PKA-Cα and -Cβ knockdown prevents A2AR-mediated Col1 increase. In contrast, A2AR represses Col3 via PKA but stimulates both Col1 and Col3 via an Epac2-dependent mechanism. A2AR stimulation with CGS21680 at 0.1 μM increased Col3 expression only upon PKA blockade. A2AR activation downstream signaling for Col1 and Col3 expression proceeds via two distinct pathways with varying sensitivity to cAMP activation; more highly cAMP-sensitive PKA activation stimulates Col1 expression, and less cAMP-sensitive Epac activation promotes both Col1 and Col3 expression. These observations may explain the dramatic change in Col1:Col3 ratio in hypertrophic and immature scars, where adenosine is present in higher concentrations than in normal skin.
Electronic supplementary material
The online version of this article (doi:10.1007/s11302-013-9368-1) contains supplementary material, which is available to authorized users.
Adenosine; Adenosine receptor A2; Collagen type I; Collagen type III; PKA; Epac
Fatty liver is commonly associated with alcohol ingestion and abuse. While the molecular pathogenesis of these fatty changes is well understood, the biochemical and pharmacological mechanisms by which ethanol stimulates these molecular changes remain unknown. During ethanol metabolism, adenosine is generated by the enzyme ecto-5′-nucleotidase, and adenosine production and adenosine receptor activation are known to play critical roles in the development of hepatic fibrosis. We therefore investigated whether adenosine and its receptors play a role in the development of alcohol-induced fatty liver. WT mice fed ethanol on the Lieber-DeCarli diet developed hepatic steatosis, including increased hepatic triglyceride content, while mice lacking ecto-5′-nucleotidase or adenosine A1 or A2B receptors were protected from developing fatty liver. Similar protection was also seen in WT mice treated with either an adenosine A1 or A2B receptor antagonist. Steatotic livers demonstrated increased expression of genes involved in fatty acid synthesis, which was prevented by blockade of adenosine A1 receptors, and decreased expression of genes involved in fatty acid metabolism, which was prevented by blockade of adenosine A2B receptors. In vitro studies supported roles for adenosine A1 receptors in promoting fatty acid synthesis and for A2B receptors in decreasing fatty acid metabolism. These results indicate that adenosine generated by ethanol metabolism plays an important role in ethanol-induced hepatic steatosis via both A1 and A2B receptors and suggest that targeting adenosine receptors may be effective in the prevention of alcohol-induced fatty liver.
Atherosclerotic cardiovascular disease (ASCVD) contributes to morbidity and mortality in systemic lupus erythematosus (SLE). Immunologic derangements may disrupt cholesterol balance in vessel wall monocytes/macrophages and endothelium. We determined whether lupus plasma impacts expression of cholesterol 27-hydroxylase, an anti-atherogenic cholesterol-degrading enzyme that promotes cellular cholesterol efflux, in THP-1 human monocytes and primary human aortic endothelial cells (HAEC). THP-1 monocytes and HAEC were incubated in medium containing SLE patient plasma or apparently healthy control human plasma (CHP). SLE plasma decreased 27-hydroxylase message in THP-1 monocytes by 47 ± 8% (p < 0.008) and in HAEC by 51 ± 5.5% (n = 5, p < 0.001). THP-1 macrophages were incubated in 25% lupus plasma or CHP and cholesterol-loaded (50 µg ml−1 acetylated low density lipoprotein). Lupus plasma more than doubled macrophage foam cell transformation (74 ± 3% vs.35 § 3% for CHP, n = 3, p < 0.001). Impaired cholesterol homeostasis in SLE provides further evidence of immune involvement in atherogenesis. Strategies to inhibit or reverse arterial cholesterol accumulation may benefit SLE patients.
Lupus erythematosus; Systemic; Atherosclerosis; Cholesterol; Macrophage scavenger receptor; Foam cells
The ability of antiinflammatory strategies to alter cardiovascular risk has not been rigorously examined. Colchicine is an antiinflammatory agent that affects macrophages, neutrophils, and endothelial cells, all of which are implicated in the pathogenesis of cardiovascular disease. We examined whether colchicine use was associated with a reduced risk of myocardial infarction (MI) in patients with gout.
We conducted a retrospective, cross-sectional study of all patients with an International Classification of Diseases, 9th ed, code for gout in the electronic medical record (EMR) of the New York Harbor Healthcare System Veterans Affairs network and ≥ 1 hospital visit between August 2007 and August 2008. Hospital pharmacy data were used to identify patients who had filled at least 1 colchicine prescription versus those who had not. Demographics and CV comorbidities were collected by EMR review. The primary outcome was diagnosis of MI. Secondary outcomes included all-cause mortality and C-reactive protein (CRP) level.
In total, 1288 gout patients were identified. Colchicine (n = 576) and no colchicine (n = 712) groups had similar baseline demographics and serum urate levels. Prevalence of MI was 1.2% in the colchicine versus 2.6% in the no-colchicine group (p = 0.03). Colchicine users also had fewer deaths and lower CRP levels, although these did not achieve statistical significance. Colchicine effects persisted when allopurinol users were excluded from the analysis.
In this hypothesis-generating study, gout patients who took colchicine had a significantly lower prevalence of MI and exhibited trends toward reduced all-cause mortality and lower CRP level versus those who did not take colchicine.
GOUT; COLCHICINE; MYOCARDIAL INFARCTION; MORTALITY; C-REACTIVE PROTEIN
Wound healing and tissue repair are critical processes, and adenosine, released from injured or ischemic tissues, plays an important role in promoting wound healing and tissue repair. Recent studies in genetically manipulated mice demonstrate that adenosine receptors are required for appropriate granulation tissue formation and in adequate wound healing. A2A and A2B adenosine receptors stimulate both of the critical functions in granulation tissue formation (i.e., new matrix production and angiogenesis), and the A1 adenosine receptor (AR) may also contribute to new vessel formation. The effects of adenosine acting on these receptors is both direct and indirect, as AR activation suppresses antiangiogenic factor production by endothelial cells, promotes endothelial cell proliferation, and stimulates angiogenic factor production by endothelial cells and other cells present in the wound. Similarly, adenosine, acting at its receptors, stimulates collagen matrix formation directly. Like many other biological processes, AR-mediated promotion of tissue repair is critical for appropriate wound healing but may also contribute to pathogenic processes. Excessive tissue repair can lead to problems such as scarring and organ fibrosis and adenosine, and its receptors play a role in pathologic fibrosis as well. Here we review the evidence for the involvement of adenosine and its receptors in wound healing, tissue repair and fibrosis.
Adenosine receptors; Wound healing; Fibrosis; Angiogenesis; Neovascularization
Low-dose methotrexate (MTX), a mainstay in the therapy of rheumatoid arthritis, is effective in only 60–70% of patients, a finding mirrored by poor anti-inflammatory efficacy in some animal models, most notably collagen-induced arthritis. To determine whether genetic factors or the model itself were responsible for the poor response to MTX we directly compared the responses of four inbred mouse strains to MTX in the air pouch model of acute inflammation.
Exudate leukocyte count and adenosine concentration were determined in inbred mice treated with methotrexate (0.75 mg/kg intraperitoneally [IP] every week for 4 weeks) or vehicle 4 hours after injection of carrageenan into the air pouch using previously described methods(1). Quantitative trait locus mapping was performed using an in silico method (2, 3) to identify loci potentially associated with each phenotype.
MTX significantly reduced the exudate leukocyte count in C57BL/6 and BALB/c, but not DBA/1 (the strain used in the collagen arthritis model) or DBA/2 mice. In a parallel fashion MTX increased adenosine concentration in inflammatory exudates of C57BL/6 and BALB/c, but not DBA/1 or DBA/2 mice. Anti-inflammatory and adenosine responses to MTX in DBA1xC57BL/6 F1 and F2 offspring were most consistent with single genetic loci being responsible for each phenotype. In silico mapping identified partially overlapping loci containing candidate genes involved in both responses.
Genetic factors contribute to the anti-inflammatory efficacy of methotrexate and a single locus involved in methotrexate-induced adenosine upregulation is likely responsible for the observed resistance to MTX in DBA/1 mice.
Adenosine, acting through the A2A receptor, promotes tissue matrix production in the skin and the liver and induces the development of dermal fibrosis and cirrhosis in murine models. Since expression of A2A receptors is increased in scleroderma fibroblasts, we examined the mechanisms by which the A2A receptor produces its fibrogenic effects.
The effects of A2A receptor ligation on the expression of the transcription factor, Fli1, a constitutive repressor for the synthesis of matrix proteins, such as collagen, is studied in dermal fibroblasts. Fli1 is also known to repress the transcription of CTGF/CCN2, and the effects of A2A receptor stimulation on CTGF and TGF-β1 expression are also examined.
A2A receptor occupancy suppresses the expression of Fli1 by dermal fibroblasts. A2A receptor activation induces the secretion of CTGF by dermal fibroblasts, and neutralization of CTGF abrogates the A2A receptor-mediated enhancement of collagen type I production. A2AR activation, however, resulted in a decrease in TGF-β1 protein release.
Our results suggest that Fli1 and CTGF are important mediators of the fibrogenic actions of adenosine and the use of small molecules such as adenosine A2A receptor antagonists may be useful in the therapy of dermal fibrosis in diseases such as scleroderma.
Fibrosis; fibroblast; scleroderma
Movement of free cholesterol between the cellular compartment and acceptor is governed by cholesterol gradients that are determined by several enzymes and reverse cholesterol transport proteins. We have previously demonstrated that adenosine A2A receptors inhibit foam cell formation and stimulate production of cholesterol 27-hydroxylase (CYP27A1), an enzyme involved in the conversion of cholesterol to oxysterols. We therefore asked whether the effect of adenosine A2A receptors on foam cell formation in vitro are mediated by CYP27A1 or apoE, a carrier for cholesterol in the serum. We found that specific lentiviral siRNA infection markedly reduced apoE or 27-hydroxylase mRNA in THP-1 cells. Despite diminished apoE expression (p< 0.0002, IFNγ CGS vs. IFNγ alone, n= 4) CGS-21680, an adenosine A2A receptor agonist, inhibits foam cell formation. In contrast, CGS-21680 had no effect on reducing foam cell formation in CYP27A1 KD cells (4±2% p<0.5113 inhibition vs. IFNγ alone n= 4). Previously we reported the A2A agonist CGS-21680 increases apoAI-mediated cholesterol efflux nearly 2-fold in wildtype macrophages. Adenosine receptor activation had no effect on cholesterol efflux in CYP27A1 KD cells but reduced efflux in apoE KD cells. These results demonstrate that adenosine A2A receptor occupancy diminishes foam cell formation by increasing expression and function of CYP27A1.
Atherosclerosis; Inflammation; Adenosine; Macrophages
Prosthesis loosening, associated with wear-particle–induced inflammation and osteoclast-mediated bone destruction, is a common cause for joint implant failure, leading to revision surgery. Adenosine A2A receptors (A2AR) mediate potent anti-inflammatory effects in many tissues and prevent osteoclast differentiation. We tested the hypothesis that an A2AR agonist could reduce osteoclast-mediated bone resorption in a murine calvaria model of wear-particle–induced bone resorption. C57Bl/6 and A2A knockout (A2ARKO) mice received ultrahigh-molecular weight polyethylene particles (UHMWPE) and were treated daily with either saline or the A2AR agonist CGS21680. After 2 weeks, micro-computed tomography of calvaria demonstrated that CGS21680 reduced particle-induced bone pitting and porosity in a dose-dependent manner, increasing cortical bone and bone volume compared to control mice. Histological examination demonstrated diminished inflammation after treatment with CGS21680. In A2AKO mice, CGS21680 did not affect osteoclast-mediated bone resorption or inflammation. Levels of bone-resorption markers receptor activator of nuclear factor-kB (RANK), RANK ligand (RANKL), cathepsin K, CD163, and osteopontin were reduced following CGS21680 treatment, together with a reduction in osteoclasts. Secretion of interleukin 1β (IL-1β) and TNFα was significantly decreased, whereas IL-10 was markedly increased in bone by CGS21680. These results in mice suggest that site-specific delivery of an adenosine A2AR agonist could enhance implant survival, delaying or eliminating the need for revision arthroplastic surgery.
Adenosine—a purine nucleoside generated extracellularly from adenine nucleotides released by cells as a result of direct stimulation, hypoxia, trauma, or metabolic stress—is a well-known physiologic and pharmacologic agent. Recent studies demonstrate that adenosine, acting at its receptors, promotes wound healing by stimulating both angiogenesis and matrix production. Subsequently, adenosine and its receptors have also been found to promote fibrosis (excess matrix production) in the skin, lungs, and liver, but to diminish cardiac fibrosis. A commonly ingested adenosine receptor antagonist, caffeine, blocks the development of hepatic fibrosis, an effect that likely explains the epidemiologic finding that coffee drinking, in a dose-dependent fashion, reduces the likelihood of death from liver disease. Accordingly, adenosine may be a good target for therapies that prevent fibrosis of the lungs, liver, and skin.
Adenosine is an endogenous autocoid that regulates a multitude of bodily functions. Its anti-inflammatory actions are well known to rheumatologists since it mediates many of the anti-inflammatory effects of a number of antirheumatic drugs such as methotrexate. However, inflammatory and tissue regenerative responses are intricately linked, with wound healing being a prime example. It has only recently been appreciated that adenosine has a key role in tissue regenerative and fibrotic processes. An understanding of these processes may shed new light on potential therapeutic options in diseases such as scleroderma where tissue fibrosis features prominently.
Adenosine receptor; Fibrosis; Collagen; Cirrhosis
adenosine; adenosine receptors; caffeine; methylxanthines
Predicting complications of diseases such as rheumatoid arthritis (RA) as well as the efficacy and toxicity of drugs used to treat the disease based on an understanding of genetic differences is leading to the development of highly individualized, personal medicine. The prevention of cardiovascular complications of RA has assumed greater importance as our ability to treat the underlying joint disease has improved and it may be possible to predict which patients with RA are at greatest risk of developing cardiovascular disease.
Psychological stress has long been associated with effects on immune function and disease. In particular, differential effects of acute and chronic stress on skin immunity occur in the rodent restraint stress model, with acute stress enhancing and chronic stress suppressing cutaneous hypersensitivity. Extracellular levels of adenosine are known to modulate diverse biological activities in the CNS and peripheral tissues and serve an important protective function against physiological stressors such as inflammation and ischemia. In this study, we utilized the restraint stress model and the skin sensitizer dinitrofluorobezene to test the hypothesis that perceived stress influences contact hypersensitivity through an adenosine A1 receptor-mediated mechanism. We subjected hapten-sensitized A1 receptor knockout (A1 KO) mice and their wild-type (WT) littermates to either acute (2.5 h) or chronic (5 h daily × 4 weeks) restraint stress, followed by hapten re-challenge of the pinna. Daily measurements of the resulting pinna swellings from each group were compared to reactions in non-stressed controls. In WT mice, pinna swelling was augmented in acutely stressed mice and suppressed in the chronically stressed group. In contrast, contact hypersensitivity responses in the A1 KO mice failed to be affected by either acute or chronic stress. Absence of the adenosine A1 receptor did not affect levels of plasma corticosterone or urine catecholamines under these stressful conditions but did lead to reduced numbers of circulating neutrophil granulocytes compared to stressed WT animals. These results suggest that the adenosine A1 receptor pathway plays a role in the process by which perceived psychological stress influences the contact hypersensitivity response.
Contract hypersensitivity; Adenosine; Adenosine receptor
Genome-wide association studies are the most comprehensive and straightforward approach to teasing out the identity of genetic polymorphisms associated with any given disease or characteristic. With the availability of DNA banks from large cohorts of ethnically matched patients and healthy individuals it is now possible to define even marginal genetic associations between genetic polymorphisms and diseases. As increasing numbers of these studies are carried out and as associations with smaller and smaller risks are identified, there is the growing concern that the findings will be of increasingly marginal value. Thus, the glut of new genetic associations is rapidly overwhelming our interest in the results, a situation that could be described as TMI (too much information). Recent genetic association studies in rheumatoid arthritis suggest that we may be approaching the TMI stage of genome-wide association studies.