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1.  Circadian rhythms in rheumatology - a glucocorticoid perspective 
Arthritis Research & Therapy  2014;16(Suppl 2):S3.
The hypothalamic-pituitary-adrenal (HPA) axis plays an important role in regulating and controlling immune responses. Dysfunction of the HPA axis has been implicated in the pathogenesis of rheumatoid arthritis (RA) and other rheumatic diseases. The impact of glucocorticoid (GC) therapy on HPA axis function also remains a matter of concern, particularly for longer treatment duration. Knowledge of circadian rhythms and the influence of GC in rheumatology is important: on the one hand we aim for optimal treatment of the daily undulating inflammatory symptoms, for example morning stiffness and swelling; on the other, we wish to disturb the HPA axis as little as possible. This review describes circadian rhythms in RA and other chronic inflammatory diseases, dysfunction of the HPA axis in RA and other rheumatic diseases and the recent concept of the hepato-hypothalamic-pituitary-adrenal-renal axis, the problem of adrenal suppression by GC therapy and how it can be avoided, and evidence that chronotherapy with modified release prednisone effective at 02:00 a.m. can inhibit proinflammatory sequelae of nocturnal inflammation better compared with GC administration in the morning but does not increase the risk of HPA axis insufficiency in RA.
PMCID: PMC4249493  PMID: 25608777
3.  Insulin resistance, selfish brain, and selfish immune system: an evolutionarily positively selected program used in chronic inflammatory diseases 
Arthritis Research & Therapy  2014;16(Suppl 2):S4.
Insulin resistance (IR) is a general phenomenon of many physiological states, disease states, and diseases. IR has been described in diabetes mellitus, obesity, infection, sepsis, trauma, painful states such as postoperative pain and migraine, schizophrenia, major depression, chronic mental stress, and others. In arthritis, abnormalities of glucose homeostasis were described in 1920; and in 1950 combined glucose and insulin tests unmistakably demonstrated IR. The phenomenon is now described in rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, polymyalgia rheumatica, and others. In chronic inflammatory diseases, cytokine-neutralizing strategies normalize insulin sensitivity. This paper delineates that IR is either based on inflammatory factors (activation of the immune/ repair system) or on the brain (mental activation via stress axes). Due to the selfishness of the immune system and the selfishness of the brain, both can induce IR independent of each other. Consequently, the immune system can block the brain (for example, by sickness behavior) and the brain can block the immune system (for example, stress-induced immune system alterations). Based on considerations of evolutionary medicine, it is discussed that obesity per se is not a disease. Obesity-related IR depends on provoking factors from either the immune system or the brain. Chronic inflammation and/or stress axis activation are thus needed for obesity-related IR. Due to redundant pathways in stimulating IR, a simple one factor-neutralizing strategy might help in chronic inflammatory diseases (inflammation is the key), but not in obesity-related IR. The new considerations towards IR are interrelated to the published theories of IR (thrifty genotype, thrifty phenotype, and others).
PMCID: PMC4249495  PMID: 25608958
4.  Interaction of the endocrine system with inflammation: a function of energy and volume regulation 
During acute systemic infectious disease, precisely regulated release of energy-rich substrates (glucose, free fatty acids, and amino acids) and auxiliary elements such as calcium/phosphorus from storage sites (fat tissue, muscle, liver, and bone) are highly important because these factors are needed by an energy-consuming immune system in a situation with little or no food/water intake (sickness behavior). This positively selected program for short-lived infectious diseases is similarly applied during chronic inflammatory diseases. This review presents the interaction of hormones and inflammation by focusing on energy storage/expenditure and volume regulation. Energy storage hormones are represented by insulin (glucose/lipid storage and growth-related processes), insulin-like growth factor-1 (IGF-1) (muscle and bone growth), androgens (muscle and bone growth), vitamin D (bone growth), and osteocalcin (bone growth, support of insulin, and testosterone). Energy expenditure hormones are represented by cortisol (breakdown of liver glycogen/adipose tissue triglycerides/muscle protein, and gluconeogenesis; water retention), noradrenaline/adrenaline (breakdown of liver glycogen/adipose tissue triglycerides, and gluconeogenesis; water retention), growth hormone (glucogenic, lipolytic; has also growth-related aspects; water retention), thyroid gland hormones (increase metabolic effects of adrenaline/noradrenaline), and angiotensin II (induce insulin resistance and retain water). In chronic inflammatory diseases, a preponderance of energy expenditure pathways is switched on, leading to typical hormonal changes such as insulin/IGF-1 resistance, hypoandrogenemia, hypovitaminosis D, mild hypercortisolemia, and increased activity of the sympathetic nervous system and the renin-angiotensin-aldosterone system. Though necessary during acute inflammation in the context of systemic infection or trauma, these long-standing changes contribute to increased mortality in chronic inflammatory diseases.
PMCID: PMC3978663  PMID: 24524669
5.  β‐Endorphin, Met‐enkephalin and corresponding opioid receptors within synovium of patients with joint trauma, osteoarthritis and rheumatoid arthritis 
Annals of the Rheumatic Diseases  2007;66(7):871-879.
Intra‐articularly applied opioid agonists or antagonists modulate pain after knee surgery and in chronic arthritis. Therefore, the expression of β‐endorphin (END), Met‐enkephalin (ENK), and μ and δ opioid receptors (ORs) within synovium of patients with joint trauma (JT), osteoarthritis (OA) and rheumatoid arthritis (RA) were examined.
Synovial samples were subjected to double immunohistochemical analysis of opioid peptides with immune cell markers, and of ORs with the neuronal markers calcitonin gene‐related peptide (CGRP) and tyrosine hydroxylase (TH).
END and ENK were expressed by macrophage‐like (CD68+) and fibroblast‐like (CD68−) cells within synovial lining layers of all disorders. In the sublining layers, END and ENK were mostly expressed by granulocytes in patients with JT, and by macrophages/monocytes, lymphocytes and plasma cells in those with OA and RA. Overall, END‐ and ENK‐immunoreactive (IR) cells were more abundant in patients with RA than in those with OA and JT. ORs were found on nerve fibres and immune cells in all patients. OR‐IR nerve fibres were significantly more abundant in patients with RA than in those with OA and JT. μORs and δORs were coexpressed with CGRP but not with TH.
Parallel to the severity of inflammation, END and ENK in immune cells and their receptors on sensory nerve terminals are more abundant in patients with RA than in those with JT and OA. These findings are consistent with the notion that, with prolonged and enhanced inflammation, the immune and peripheral nervous systems upregulate sensory nerves expressing ORs and their ligands to counterbalance pain and inflammation.
PMCID: PMC1955126  PMID: 17324971
6.  Role of HSP-90 for increased nNOS-mediated vasodilation in mesenteric arteries in portal hypertension 
AIM: To explore the role of heat shock protein-90 (HSP-90) for nitrergic vasorelaxation in the splanchnic circulation in rats with and without portal hypertension.
METHODS: Neuronal nitric oxide synthase (nNOS) and HSP-90 were analyzed by immunofluorescence, western blotting and co-immunoprecipitation in the mesenteric vasculature and isolated nerves of portal-vein-ligated (PVL) rats and sham operated rats. In vitro perfused de-endothelialized mesenteric arterial vasculature was preconstricted with norepinephrine (EC80) and tested for nNOS-mediated vasorelaxation by periarterial nerve stimulation (PNS, 2-12 Hz, 45V) before and after incubation with geldanamycin (specific inhibitor of HSP-90 signalling, 3 μg/mL) or L-NAME (non-specific NOS-blocker, 10-4 mol/L).
RESULTS: nNOS and HSP-90 expression was significantly increased in mesenteric nerves from PVL as compared to sham rats. Moreover, nNOS and HSP-90 were visualized in mesenteric nerves by immunofluorescence and immunoprecipitation of nNOS co-immunoprecitated HSP-90 in sham and PVL rats. PNS induced a frequency-dependent vasorelaxation which was more pronounced in PVL as compared to sham rats. L-NAME and geldanamycin markedly reduced nNOS-mediated vasorelaxation abrogating differences between the study groups. The effect of L-NAME and geldanamycin on nNOS-mediated vasorelaxation was significantly greater in PVL than in sham animals. However, no difference in magnitude of effect between L-NAME and geldanamycin was noted.
CONCLUSION: HSP-90 acts as a signalling mediator of nNOS-dependent nerve mediated vascular responses in mesenteric arteries, and the increased nitrergic vasorelaxation observed in portal hypertension is mediated largely by HSP-90.
PMCID: PMC2856823  PMID: 20397260
Heat shock protein-90; Nitric oxide; Vasodilation; Portal hypertension; Mesenteric circulation
7.  Chemical Sympathectomy Increases Susceptibility to Ocular Herpes Simplex Virus Type 1 Infection 
Journal of neuroimmunology  2008;197(1):37-46.
The cornea is one of the most highly innervated tissues in the mammalian host. We hypothesized changes to cornea innervation through chemical sympathectomy would significantly alter the host response to the neurotropic viral pathogen, herpes simplex virus type 1 (HSV-1) following ocular infection. Mice treated with 6-hydroxydopamine hydrobromide displayed reduced tyrosine hydroxylase-positive fibers residing in the cornea. Sympathectomized mice were also found to show a transient rise in virus recovered in infected tissues and succumbed to infection in greater numbers. Whereas there were no differences in infiltrating leukocyte populations including HSV-1-specific cytotoxic T lymphocytes in the infected tissue, an increase in substance P and a decrease in IFN-γ levels in the trigeminal ganglion but not brain stem of sympathectomized mice were noted. Sympathectomized mice treated with the neurokinin-1 receptor antagonist L703,606 had delayed mortality implicating the involvement of substance P in HSV-1-mediated death.
PMCID: PMC2435389  PMID: 18495255
herpes Simplex Virus 1; 6-hydroxydopamine; substance P
8.  B Cell Activating Factor of the Tumor Necrosis Factor Family (BAFF) Behaves as an Acute Phase Reactant in Acute Pancreatitis 
PLoS ONE  2013;8(1):e54297.
To determine if B cell activating factor of the tumor necrosis factor family (BAFF) acts as an acute phase reactant and predicts severity of acute pancreatitis.
40 patients with acute pancreatitis were included in this single center cohort pilot study. Whole blood and serum was analyzed on day of admission and nine consecutive days for BAFF, c-reactive protein (CRP), interleukin-6 (IL-6), procalcitonin (PCT), and leucocyte numbers. Different severity Scores (Ranson, APACHE II, SAPS II, SAPS III) and the clinical course of the patient (treatment, duration of stay, duration ICU) were recorded.
Serum BAFF correlates with CRP, an established marker of severity in acute pancreatitis at day of admission with a timecourse profil similar to IL-6 over the first nine days. Serum BAFF increases with Ranson score (Kruskal-Wallis: Chi2 = 10.8; p = 0.03) similar to CRP (Kruskal-Wallis: Chi2 = 9.4; p = 0.05 ). Serum BAFF, IL-6, and CRP levels are elevated in patients that need intensive care for more than seven days and in patients with complicated necrotizing pancreatitis. Discriminant analysis and receiver operator characteristics show that CRP (wilks-lambda = 0.549; ROC: AUC 0.948) and BAFF (wilks-lambda = 0.907; ROC: AUC 0.843) serum levels at day of admission best predict severe necrotizing pancreatitis or death, outperforming IL-6, PCT, and number of leucocytes.
This study establishes for the first time BAFF as an acute phase reactant with predictive value for the course of acute pancreatitis. BAFF outperforms established markers in acute pancreatitis, like IL-6 and PCT underscoring the important role of BAFF in the acute inflammatory response.
PMCID: PMC3544799  PMID: 23342125
9.  Energy metabolism and rheumatic diseases: from cell to organism 
In rheumatic and other chronic inflammatory diseases, high amounts of energy for the activated immune system have to be provided and allocated by energy metabolism. In recent time many new insights have been gained into the control of the immune response through metabolic signals. Activation of immune cells as well as reduced nutrient supply and hypoxia in inflamed tissues cause stimulation of glycolysis and other cellular metabolic pathways. However, persistent cellular metabolic signals can promote ongoing chronic inflammation and loss of immune tolerance. On the organism level, the neuroendocrine immune response of the hypothalamic-pituitary adrenal axis and sympathetic nervous system, which is meant to overcome a transient inflammatory episode, can lead to metabolic disease sequelae if chronically activated. We conclude that, on cellular and organism levels, a prolonged energy appeal reaction is an important factor of chronic inflammatory disease etiology.
PMCID: PMC3446535  PMID: 22747923
10.  Disruption of rhythms of molecular clocks in primary synovial fibroblasts of patients with osteoarthritis and rheumatoid arthritis, role of IL-1β/TNF 
Arthritis Research & Therapy  2012;14(3):R122.
Circadian rhythms play an important role in the body and in single cells. Rhythms of molecular clocks have not been investigated in synovial fibroblasts (SF) of patients with osteoarthritis (OA) and rheumatoid arthritis (RA). The study was initiated to fill this gap and to study effects of interleukin (IL)-1β/tumor necrosis factor (TNF) on rhythmicity in synovial fibroblasts of RA and OA patients.
The presence of BMAL-1, CLOCK, Period 1 and Period 2 proteins in synovial tissue was investigated by immunofluorescence. The presence of mRNA of molecular clocks was studied during 72 h by qPCR. Characteristics of rhythms were studied with time series analysis.
BMAL-1, CLOCK, Period 1 and Period 2 proteins were abundantly present in synovial tissue of OA, RA and controls. Receiving synovial tissue at different operation time points during the day (8:00 am to 4:00 pm) did not reveal a rhythm of BMAL-1 or Period 1 protein. In OASF and RASF, no typical rhythm curve of molecular clock mRNA was observed. Time series analysis identified a first peak between 2 and 18 hours after synchronization but a period was not detectable due to loss of rhythm. TNF inhibited mRNA of CLOCK, Period 1 and Period 2 in OASF, while IL-1β and TNF increased these factors in RASF. This was supported by dose-dependently increased levels in MH7A RA fibroblasts. In RASF, IL-1β and TNF shifted the first peak of BMAL-1 mRNA to later time points (8 h to 14 h).
Rhythmicity is not present in primary OASF and RASF, which is unexpected because fibroblasts usually demonstrate perfect rhythms during several days. This might lead to uncoupling of important cellular pathways.
PMCID: PMC3446503  PMID: 22621205
11.  Integrins and their ligands in rheumatoid arthritis 
Integrins play an important role in cell adhesion to the extracellular matrix and other cells. Upon ligand binding, signaling is initiated and several intracellular pathways are activated. This leads to a wide variety of effects, depending on cell type. Integrin activation has been linked to proliferation, secretion of matrix-degrading enzymes, cytokine production, migration, and invasion. Dysregulated integrin expression is often found in malignant disease. Tumors use integrins to evade apoptosis or metastasize, indicating that integrin signaling has to be tightly controlled. During the course of rheumatoid arthritis, the synovial tissue is infiltrated by immune cells that secrete large amounts of cytokines. This pro-inflammatory milieu leads to an upregulation of integrin receptors and their ligands in the synovial tissue. As a consequence, integrin signaling is enhanced, leading to enhanced production of matrix-degrading enzymes and cytokines. Furthermore, in analogy to invading tumors, synovial fibroblasts start invading and degrading cartilage, thereby generating extracellular matrix debris that can further activate integrins.
PMCID: PMC3308078  PMID: 22077951
12.  Evolutionary medicine and chronic inflammatory state—known and new concepts in pathophysiology 
During the last 10 years, a series of exciting observations has led to a new theory of pathophysiology using insights from evolutionary biology and neuroendocrine immunology to understand the sequelae of chronic inflammatory disease. According to this theory, disease sequelae can be explained based on redirection of energy-rich fuels from storage organs to the activated immune system. These disease sequelae are highly diverse and include the following: sickness behavior, anorexia, malnutrition, muscle wasting–cachexia, cachectic obesity, insulin resistance with hyperinsulinemia, dyslipidemia, increase of adipose tissue near inflamed tissue, alterations of steroid hormone axes, elevated sympathetic tone and local sympathetic nerve fiber loss, decreased parasympathetic tone, hypertension, inflammation-related anemia, and osteopenia. Since these disease sequelae can be found in many animal models of chronic inflammatory diseases with mammals (e.g., monkeys, mice, rats, rabbits, etc.), the evolutionary time line goes back at least 70 million years. While the initial version of this theory could explain prominent sequelae of chronic inflammatory disease, it did not however address two features important in the pathogenesis of immune-mediated diseases: the time point when an acute inflammatory disease becomes chronic, and the appearance of hypertension in chronic inflammation. To address these aspects more specifically, a new version of the theory has been developed. This version defines more precisely the moment of transition from acute inflammatory disease to chronic inflammatory disease as a time in which energy stores become empty (complete energy consumption). Depending on the amount of stored energy, this time point can be calculated to be 19–43 days. Second, the revised theory addresses the mechanisms of essential hypertension since, on the basis of water loss, acute inflammatory diseases can stimulate water retention using a positively selected water retention system (identical to the energy provision system). In chronic smoldering inflammation, however, there is no increased water loss. In contrast, there is increased water generation in inflamed tissue and inflammatory cells, and the activation of the water retention system persists. This combination leads to a net increase of the systemic fluid volume, which is hypothesized to be the basis of essential hypertension (prevalence in adults 22–32%).
PMCID: PMC3354326  PMID: 22271169
Hormone; Autoimmunity; System biology
13.  Restoring the Balance of the Autonomic Nervous System as an Innovative Approach to the Treatment of Rheumatoid Arthritis 
Molecular Medicine  2011;17(9-10):937-948.
The immunomodulatory effect of the autonomic nervous system has raised considerable interest over the last decades. Studying the influence on the immune system and the role in inflammation of the sympathetic as well as the parasympathetic nervous system not only will increase our understanding of the mechanism of disease, but also could lead to the identification of potential new therapeutic targets for chronic immune-mediated inflammatory diseases, such as rheumatoid arthritis (RA). An imbalanced autonomic nervous system, with a reduced parasympathetic and increased sympathetic tone, has been a consistent finding in RA patients. Studies in animal models of arthritis have shown that influencing the sympathetic (via α- and β-adrenergic receptors) and the parasympathetic (via the nicotinic acetylcholine receptor α7nAChR or by electrically stimulating the vagus nerve) nervous system can have a beneficial effect on inflammation markers and arthritis. The immunosuppressive effect of the parasympathetic nervous system appears less ambiguous than the immunomodulatory effect of the sympathetic nervous system, where activation can lead to increased or decreased inflammation depending on timing, doses and kind of adrenergic agent used. In this review we will discuss the current knowledge of the role of both the sympathetic (SNS) and parasympathetic nervous system (PNS) in inflammation with a special focus on the role in RA. In addition, potential antirheumatic strategies that could be developed by targeting these autonomic pathways are discussed.
PMCID: PMC3188868  PMID: 21607292
14.  The oncofetal gene survivin is re-expressed in osteoarthritis and is required for chondrocyte proliferation in vitro 
Regulation of cell death and cell division are key processes during chondrogenesis and in cartilage homeostasis and pathology. The oncogene survivin is considered to be critical for the coordination of mitosis and maintenance of cell viability during embryonic development and in cancer, and is not detectable in most adult differentiated tissues and cells. We analyzed survivin expression in osteoarthritic cartilage and its function in primary human chondrocytes in vitro.
Survivin expression was analyzed by immunoblotting and quantitative real-time PCR. The localization was visualized by immunofluorescence. Survivin functions in vitro were investigated by transfection of a specific siRNA.
Survivin was expressed in human osteoarthritic cartilage, but was not detectable in macroscopically and microscopically unaffected cartilage of osteoarthritic knee joints. In primary human chondrocyte cultures, survivin was localized to heterogeneous subcellular compartments. Suppression of survivin resulted in inhibition of cell cycle progression and sensitization toward apoptotic stimuli in vitro.
The present study indicates a role for survivin in osteoarthritic cartilage and human chondrocytes. In vitro experiments indicated its involvement in cellular division and viability. Learning more about the functions of survivin in chondrocyte biology might further help toward understanding and modulating the complex processes of cartilage pathology and regeneration.
PMCID: PMC3141611  PMID: 21729321
apoptosis; chondrocyte; osteoarthritis; proliferation; survivin
15.  Tumor necrosis factor and norepinephrine lower the levels of human neutrophil peptides 1-3 secretion by mixed synovial tissue cultures in osteoarthritis and rheumatoid arthritis 
Arthritis Research & Therapy  2010;12(3):R110.
Neutrophils and monocytes play an important role in overt inflammation in chronic inflammatory joint diseases such as rheumatoid arthritis (RA). The sympathetic nervous system (SNS) inhibits many neutrophil/monocyte functions and macrophage tumor necrosis factor (TNF), but because of the loss of sympathetic nerve fibers in inflamed tissue, sympathetic control is attenuated. In this study, we focused on noradrenergic and TNF regulation of human neutrophil peptides 1-3 (HNP1-3), which are proinflammatory bactericidal α-defensins.
Synovial tissue and cells were obtained from patients with RA and osteoarthritis (OA). By using immunohistochemistry and immunofluorescence, HNP1-3 were tracked in the tissue. With synovial cell-culture experiments and ELISA, effects of norepinephrine, TNF, and cortisol on HNP1-3 were detected.
HNP1-3 were abundantly expressed in the synovial lining and adjacent sublining area but not in deeper layers of synovial tissue. The human β-defensin-2, used as control, was hardly detectable in the tissue and in supernatants. HNP1-3 double-stained with neutrophils but not with macrophages, fibroblasts, T/B lymphocytes, and mast cells. Norepinephrine dose-dependently decreased HNP1-3 levels from RA and OA cells. TNF also inhibited HNP1-3 levels from OA but not from RA cells. Cortisol inhibited HNP1-3 levels only in OA patients. A combination of norepinephrine and cortisol did not show additive or synergistic effects.
This study demonstrated an inhibitory effect of norepinephrine on HNP1-3 of mixed synovial cells. In light of these findings, the loss of sympathetic nerve fibers with low resting norepinephrine levels might also augment the inflammatory process through HNP1-3.
PMCID: PMC2911901  PMID: 20525314
16.  Insights into endocrine-immunological disturbances in autoimmunity and their impact on treatment 
The neuroendocrine immune (NEI) system is regarded as a fundamental network for the maintenance of health status (homeostasis), and it plays an important role in several systemic diseases, including autoimmune disorders. Among the major players of NEI pathways are steroid hormones of the adrenal (cortisol) and gonadal glands (sex hormones), neurohormones such as melatonin, and more recently the vitamin D endocrine system. Estrogens, melatonin and chronic stress (inducing decreased adrenal glucocorticoid release over a long time) strongly modulate the NEI system and stimulate the immune response. The vitamin D endocrine system is regarded as a potential immunosuppressive factor. Consequently, estrogens (especially in patients affected by B-cell-driven immunity) and melatonin should be avoided, and glucocorticoids (as replacement therapy) and vitamin D are allowed in the treatment of autoimmunity.
PMCID: PMC2688171  PMID: 19435479
17.  Stress of different types increases the proinflammatory load in rheumatoid arthritis 
Stress in patients with chronic inflammatory diseases such as rheumatoid arthritis (RA) stimulates proinflammatory mechanisms due to the defect of stress response systems (for example, the sympathetic nervous system and the hypothalamic–pituitary–adrenal axis). Among other mechanisms, the loss of sympathetic nerve fibers in inflamed tissue and inadequate cortisol secretion in relation to inflammation lead to an enhanced proinflammatory load in RA. Stress and the subsequent stimulation of inflammation (systemic and local) lead to increased sensitization of pain and further defects of stress response systems (vicious cycle of stress, pain, and inflammation).
PMCID: PMC2714129  PMID: 19591636
18.  Association of common polymorphisms in known susceptibility genes with rheumatoid arthritis in a Slovak population using osteoarthritis patients as controls 
Both genetic and environmental factors contribute to rheumatoid arthritis (RA), a common and complex autoimmune disease. As well as the major susceptibility gene HLA-DRB1, recent genome-wide and candidate-gene studies reported additional evidence for association of single nucleotide polymorphism (SNP) markers in the PTPN22, STAT4, OLIG3/TNFAIP3 and TRAF1/C5 loci with RA. This study was initiated to investigate the association between defined genetic markers and RA in a Slovak population. In contrast to recent studies, we included intensively-characterized osteoarthritis (OA) patients as controls.
We used material of 520 RA and 303 OA samples in a case-control setting. Six SNPs were genotyped using TaqMan assays. HLA-DRB1 alleles were determined by employing site-specific polymerase chain reaction (PCR) amplification.
No statistically significant association of TRAF1/C5 SNPs rs3761847 and rs10818488 with RA was detected. However, we were able to replicate the association signals between RA and HLA-DRB1 alleles, STAT4 (rs7574865), PTPN22 (rs2476601) and OLIG3/TNFAIP3 (rs10499194 and rs6920220). The strongest signal was detected for HLA-DRB1*04 with an allelic P = 1.2*10-13 (OR = 2.92, 95% confidence interval (CI) = 2.18 – 3.91). Additionally, SNPs rs7574865STAT4 (P = 9.2*10-6; OR = 1.71, 95% CI = 1.35 – 2.18) and rs2476601PTPN22 (P = 9.5*10-4; OR = 1.67, 95% CI = 1.23 – 2.26) were associated with susceptibility to RA, whereas after permutation testing OLIG3/TNFAIP3 SNPs rs10499194 and rs6920220 missed our criteria for significance (Pcorr = 0.114 and Pcorr = 0.180, respectively).
In our Slovak population, HLA-DRB1 alleles as well as SNPs in STAT4 and PTPN22 genes showed a strong association with RA.
PMCID: PMC2714116  PMID: 19445664
19.  Failure of catecholamines to shift T-cell cytokine responses toward a Th2 profile in patients with rheumatoid arthritis 
To further understand the role of neuro-immunological interactions in the pathogenesis of rheumatoid arthritis (RA), we studied the influence of sympathetic neurotransmitters on cytokine production of T cells in patients with RA. T cells were isolated from peripheral blood of RA patients or healthy donors (HDs), and stimulated via CD3 and CD28. Co-incubation was carried out with epinephrine or norepinephrine in concentrations ranging from 10-5 M to 10-11 M. Interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-4, and IL-10 were determined in the culture supernatant with enzyme-linked immunosorbent assay. In addition, IFN-γ and IL-10 were evaluated with intracellular cytokine staining. Furthermore, basal and agonist-induced cAMP levels and catecholamine-induced apoptosis of T cells were measured. Catecholamines inhibited the synthesis of IFN-γ, TNF-α, and IL-10 at a concentration of 10-5 M. In addition, IFN-γ release was suppressed by 10-7 M epinephrine. Lower catecholamine concentrations exerted no significant effect. A reduced IL-4 production upon co-incubation with 10-5 M epinephrine was observed in RA patients only. The inhibitory effect of catecholamines on IFN-γ production was lower in RA patients as compared with HDs. In RA patients, a catecholamine-induced shift toward a Th2 (type 2) polarised cytokine profile was abrogated. Evaluation of intracellular cytokines revealed that CD8-positive T cells were accountable for the impaired catecholaminergic control of IFN-γ production. The highly significant negative correlation between age and catecholamine effects in HDs was not found in RA patients. Basal and stimulated cAMP levels in T-cell subsets and catecholamine-induced apoptosis did not differ between RA patients and HDs. RA patients demonstrate an impaired inhibitory effect of catecholamines on IFN-γ production together with a failure to induce a shift of T-cell cytokine responses toward a Th2-like profile. Such an unfavorable situation is a perpetuating factor for inflammation.
PMCID: PMC1779439  PMID: 16889669
20.  Androgen conversion in osteoarthritis and rheumatoid arthritis synoviocytes – androstenedione and testosterone inhibit estrogen formation and favor production of more potent 5α-reduced androgens 
Arthritis Research & Therapy  2005;7(5):R938-R948.
In synovial cells of patients with osteoarthritis (OA) and rheumatoid arthritis (RA), conversion products of major anti-inflammatory androgens are as yet unknown but may be proinflammatory. Therefore, therapy with androgens in RA could be a problem. This study was carried out in order to compare conversion products of androgens in RA and OA synoviocytes. In 26 OA and 24 RA patients, androgen conversion in synovial cells was investigated using radiolabeled substrates and analysis by thin-layer chromatography and HPLC. Aromatase expression was studied by immunohistochemistry. Dehydroepiandrosterone (DHEA) was converted into androstenediol, androstenedione (ASD), 16αOH-DHEA, 7αOH-DHEA, testosterone, estrone (E1), estradiol (E2), estriol (E3), and 16αOH-testosterone (similar in OA and RA). Surprisingly, levels of E2, E3, and 16α-hydroxylated steroids were as high as levels of testosterone. In RA and OA, 5α-dihydrotestosterone increased conversion of DHEA into testosterone but not into estrogens. The second androgen, ASD, was converted into 5α-dihydro-ASD, testosterone, and negligible amounts of E1, E2, E3, or 16αOH-testosterone. 5α-dihydro-ASD levels were higher in RA than OA. The third androgen, testosterone, was converted into ASD, 5α-dihydro-ASD, 5α-dihydrotestosterone, and negligible quantities of E1 and E2. 5α-dihydrotestosterone was higher in RA than OA. ASD and testosterone nearly completely blocked aromatization of androgens. In addition, density of aromatase-positive cells and concentration of released E2, E3, and free testosterone from superfused synovial tissue was similar in RA and OA but estrogens were markedly higher than free testosterone. In conclusion, ASD and testosterone might be favorable anti-inflammatory compounds because they decrease aromatization and increase anti-inflammatory 5α-reduced androgens. In contrast, DHEA did not block aromatization but yielded high levels of estrogens and proproliferative 16α-hydroxylated steroids. Androgens were differentially converted to pro- and anti-inflammatory steroid hormones via diverse pathways.
PMCID: PMC1257423  PMID: 16207335

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