Alpha Antagonists Research Articles

Synthesis, molecular docking, and antitumoral activity of alnustone-like compounds against estrogen receptor alpha-positive human breast cancer

Alnustone-like compounds are promising inhibitors for estrogen receptor \alpha (ER-\alpha), which is a novel cancer therapeutic target. Therefore, 10 alnustone-like compounds with substituents at the phenyl rings were synthesized by condensation of 4-phenyl-2-butanones and cinnamaldehydes via in situ enamination. The compounds displayed either protective activity or inhibited cell growth and proliferation of human breast cancer cells. Molecular docking studies indicated that the synthesized compounds interact with ER-\alpha efficiently. In this work, the protective and inhibitive roles of the synthesized compounds were related to their functional groups and to their binding mode of action on ER-\alpha protein. The compounds are potential drug candidates as ER-\alpha antagonists.

Ankylosing Spondylitis in Association with Non-Hodgkin's Lymphoma : Successful Anti-TNF Alpha Treatment

Some rheumatic diseases, including ankylosing spondylitis, appear to be associated to an increased risk of cancer, in particular lymphoma. At the same time, a slightly higher risk of cancer has been associated to Tumour Necrosis Factor (TNF)-alpha antagonists, a widely used treatment for ankylosing spondylitis. A history of malignancy is generally considered a contraindication to TNF-alpha inhibitor and, if neoplasia is uncovered during treatment, therapy suspension is mandatory. Few data are available regarding the possibility of resuming treatment in the event of a flare up of this disease, even when exams monitoring the neoplastic disease are negative. Here we describe the case of a 56-year-old AS patient who developed a cutaneous B-cell non-Hodgkin lymphoma while undergoing treatment with a TNF-alpha inhibitor. The therapy was suspended while he was treated for the neoplasia, but it was resumed when there was a flare up of the disease, and the patient showed improvement.

Pustular eruption induced by etanercept in ankylosing spondylitis patient: a rare side effect

Etanercept is a tumor necrosis factor alpha (TNF-a) antagonist with anti-inflammatory effects. It is used in the treatment of dermatologic and rheumatologic diseases such as rheumatoid arthritis, polyarticular juvenile rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. However, etanercept has various cutaneous and systemic side effects. Herein, we report a case of generalized pustular eruption due to etanercept therapy in an ankylosing spondylitis patient and review pustular diseases.

Selective Alpha7 Nicotinic Receptor Agonist Increases Cardiac Function in Isolated Mouse Hearts by a Non-Nicotinic Mechanism

Selective alpha7 nicotinic receptor agonists, such as GTS-21, are known to have neuroprotective and anti-inflammatory actions, but the effect of these agents on the heart is not known. Therefore, we evaluated the actions of GTS-21 in isolated atria and isolated hearts from C57BL/6 mice. GTS-21 (1-100 μM) caused a concentration-dependent increase in amplitude of contractions and decrease in beating rate in isolated atria. Percent changes in rate and contractile force evoked by 30 μM GTS-21 were −14 ± 2 and +36 ± 11, respectively (n = 4). The onset of responses to GTS-21 was slower than would occur to acetylcholine and norepinephrine, and effects of GTS-21 were not blocked by atropine or atenolol. The impact of GTS-21 on left ventricular function was evaluated next in isolated hearts paced at 400 BPM. Treatment with 30 µM GTS-21 caused significant increases in contractile function: developed pressure (+30 ± 4%); peak systolic pressure (+16 ± 2%); dP/dtmax (+31 ± 6%). Diastolic pressure was also decreased (−60 ± 10%) while the rate of relaxation increased (-dP/dtmax, +36 ± 6%) with no sizable change in coronary perfusion pressure (p < 0.05 for all parameters, n = 4). Surprisingly, responses to GTS-21 were not affected by a selective alpha7 antagonist or the nonselective nicotinic antagonist mecamylamine, and there was no evidence of desensitization. Our data demonstrate that GTS enhances atrial and ventricular contractility and improves LV relaxation with a modest decrease in heart rate. GTS-21 cardiac actions occur by a mechanism that is independent of nicotinic receptors and autonomic nerves. The unique profile of cardiac effects for GTS-21 suggests its potential use in the setting of acute heart failure.

Inguinal Herniation of the Urinary Bladder Presenting as Recurrent Urinary Retention.

Herniation of the urinary bladder into the inguinal canal is an uncommon finding, observed in 0.5–4% of inguinal hernias (Curry (2000)). It is usually associated with other conditions that increase intra-abdominal pressure such as bladder neck obstruction due to prostatic hypertrophy. Consequently, in men, it is usually associated with some degree of urinary retention. We present a 42-year-old man in whom herniation of the urinary bladder was the cause of urinary retention, and not vice versa. The patient was on tumor necrosis factor alpha antagonist (TNFA) (Etanercept) for severe Ankylosing spondylitis. Initially, the urinary retention was thought to be a side effect of the medication, but after the drug was discontinued, urinary retention persisted. CT and MRI demonstrated huge herniation of the urinary bladder into the inguinal canal. Immediately after the hernia was repaired, bladder function was restored. TNF treatment was restarted, and no further urinary symptoms were observed in the next two years of follow-up. In this case, the primary illness and its treatment were distracting barriers to early diagnosis and treatment. In younger patients with a large hernia who develop unexpected urinary retention, herniation of the urinary bladder should be highly considered in the differential diagnosis.

English

Tumour necrosis factor alpha (TNFα) antagonists are biological response modifiers increasingly used to effectively treat a wide array of inflammatory diseases such as Crohn’s disease and rheumatoid arthritis. Anti-TNFα agents are also used in the treatment of steroidrefractory granulomatous diseases, with reported success. Paradoxically, an increasing number of cases of anti-TNF–induced sarcoidosis are being reported. The acute form of sarcoidosis, Lofgren syndrome, is characterized by mediastinal adenopathy, erythema nodosum, arthralgia, and fever. This article describes the case of a patient with Crohn's disease who developed Lofgren syndrome during treatment with infliximab. To our knowledge, this is the first case of Lofgren syndrome developing during treatment with a TNFα antagonist.

Are alpha-1 antagonists (alpha-blockers) effective for preventing recurrent acute urinary retention in adult men?

Are alpha-1 antagonists (alpha-blockers) effective for preventing recurrent acute urinary retention in adult men?

A review of clinical approaches to antagonism of alpha2‐adrenoreceptor agonists in the horse

SummaryAlpha2‐adrenoceptor agonists xylazine, romifidine, detomidine and, in some cases, medetomidine and dexmedetomidine, are fundamental drugs used in equine practice. There are situations where the undesirable pharmacodynamic effects (ataxia, prolonged sedation, bradycardia and ileus) or accidental overdose of these drugs may need to be antagonised. The α2‐adrenoceptor antagonists tolazoline, yohimbine and atipamezole can be used to antagonise undesirable effects. However, despite being effective, α2‐adrenoceptor antagonists are also not without undesirable pharmacodynamic effects. Excitement, muscle trembling and triggered inappropriate stress responses are a few of the more serious undesirable effects. Horses demonstrate a variable response to the antagonists thus recommending dose rates become fraught with difficulty. It is therefore recommended that the α2‐adrenoceptor antagonist should be titrated to the desired clinical effect. Consequently, other reversal agents, such as anticholinergics (atropine, glycopyrrolate and hyoscine), have been administered for the treatment of α2‐adrenoceptor agonist‐induced bradycardia. Anticholinergics cannot be recommended for routine use in horses due to the undesirable cardiovascular effects and potentiation of α2‐adrenoceptor agonist‐induced gastrointestinal hypomotility. Novel peripheral acting α2‐adrenoceptor antagonists, such as MK‐467, are currently under scrutiny in veterinary anaesthesia in an effort to antagonise the undesirable effects of α2‐adrenoceptor agonists without compromising on the level of sedation. This review examines the current literature on the α2‐adrenoceptor antagonists used in horses and makes recommendations on how to use these drugs safely in an attempt to prevent undesirable pharmacodynamic effects.

Prolonged paradoxical reaction to antituberculous treatment after discontinuation of TNF-alpha- blocker therapy with adalimumab. Rare clinical documentation

In the past decades, tumor necrosis factor alpha (TNF-a) antagonist has been a milestone in the treatment of many chronic inflammatory diseases. TNF antagonist can increase patients’ susceptibility to many different kinds of infections especially those requiring granuloma formations despite regular performance of Screening for latent tuberculosis infection (LTBI). We report 2 cases of patients who developed tuberculosis under treatment with adalimumab, which was discontinued after the diagnosis of tuberculosis. During the tuberculosis therapy they unexpectedly developed a prolonged paradoxical reaction. In both cases we were only able to manage the progress of the paradoxical reaction through high steroid doses. Patients undergoing therapy with TNF- alpha-blocker are prone to develop tuberculosis infection, which could in turn lead to severe prolonged paradoxical reaction during anti-tuberculous treatment. An increased steroid dose may be required and is sometimes necessary.

Abstract 516: Intestinal Cell Gastrin Secretion is Regulated by a Sodium-Induced Increase in PPAR-A that is Mediated by Dopaminergic Stimulation

Recently a novel gastro-renal axis has been discovered for the regulation of renal sodium excretion at the moment of sodium ingestion. Cells in the digestive track secrete gastrin in response to sodium ingestion which stimulates an increase in renal sodium excretion. Dopamine is largely responsible for the regulation of sodium excretion in the kidney, and has also been shown to decrease sodium transport in intestines. We hypothesized that dopamine might also be involved with the regulation of gastrin secretion in a human intestinal gastrin secreting cell line (SW626, ATCC, Manassas VA) that also contains dopaminergic receptors. We used the ionophore monensin (MON) to increase intracellular sodium in SW626 cells in order to simulate an oral sodium load. We also stimulated the cells with the dopaminergic agonist SKF38393 (SKF, D 1 -like receptor agonist). These two manipulations (compared to vehicle VEH) caused increased relative gene expression of gastrin (ΔΔCt gastrin to actin, VEH 0.00638±0.00283; MON 0.3913372±0.0985926; SKF 0.2139286±0.0253672; P&lt;0.01 VEH vs MON or SKF, N=6 per group). Peroxisome proliferator-activated receptor-alpha (PPAR-α) associates with the gastrin transcriptional promoter by CHIP-SEQ (ENCODE database) and PPAR-α activation by fenofibrate (FENO) has been shown to reduce blood pressure and increase sodium excretion. We hypothesized that PPAR alpha would increase gastrin expression. FENO increased the immunoreactive gastrin and this effect was blocked by a PPAR alpha antagonist GW6471 (VEH 16,440±2,438 RFU; FENO 42,639±4,891; FENO+GW 19,367±1,865; P&lt;0.001 VEH vs FENO and FENO vs FENO+GW). Stimulation with MON or SKF also significantly stimulated the production of immunoreactive gastrin (VEH 16,440±2,438 RFU; MON 22,345±935; SKF 24,386±1,124; GW alone 10,235±1,214; P&lt;0.05 VEH vs MON, SKF, or GW, N=6). SW626 appear to secrete gastrin, therefore we tested the ability of secreted gastrin obtained from the media bathing SW626 cells to bind to i22 human renal proximal tubule cells (RPTC). After incubation of i22 RPTC in SW626 media for 24 hours, we detected surface gastrin staining on the i22 RPTC. We conclude that gastrin is produced by SW626 cells, is secreted into the growth media, and can bind to cell surface receptors on RPTC.

Rationally designed less toxic SPD-304 analogs and preliminary evaluation of their TNF inhibitory effects.

SPD-304 was discovered as a promising tumor necrosis factor alpha (TNF) antagonist that promotes dissociation of TNF trimers and therefore blocks the interaction of TNF and its receptor. However, SPD-304 contains a potentially toxic 3-alkylindole moiety, which can be bioactivated to a reactive electrophilic intermediate. A series of SPD-304 analogs was synthesized with the aim to diminish its toxicophore groups while maintaining the binding affinity for TNF. Incorporation of electron-withdrawing substituents at the indole moiety, in conjunction with elimination of the 6'-methyl group of the 4-chromone moiety, led to a significantly less toxic and equally potent TNF inhibitor.

Haemodynamic interactions of medetomidine and the peripheral alpha-2 antagonist MK-467 during step infusions in isoflurane-anaesthetised dogs

The haemodynamic interactions of a step infusion with medetomidine (MED) and the peripherally acting alpha-2 antagonist MK-467 (MK) were compared with MED infused alone in isoflurane-anaesthetised dogs. Eight purposely-bred Beagles were used in a randomised crossover study. Anaesthesia was induced with propofol intravenously (IV) and maintained with isoflurane in oxygen. Dogs received 1.25 µg/kg MED as a 1 min loading dose IV, along with a step-down MED infusion at rates of 8.0 µg/kg/h (step 1: 0–20 min), 5.5 µg/kg/h (step 2: 20–40 min) and 4.0 µg/kg/h (step 3: 40–95 min). Five minutes after starting the MED infusion, the dogs received MK-467 in a step-up infusion at rates of 100 µg/kg/h (step 1: 5–35 min), 200 µg/kg/h (step 2: 35–65 min) and 500 µg/kg/h (step 3: 65–95 min). Heart rate (HR), systolic (SAP) and mean arterial (MAP) blood pressures and arteriovenous oxygen content differences (a-vO2 diff) were calculated. Plasma drug concentrations were analysed. Repeated-measures general linear mixed models with Bonferroni correction were used for statistical analyses.MED infusion alone increased SAP maximally by 24.9%, MAP by 34.7% and a-vO2 diff by 222.5%, and reduced HR by 32.3%, but these changes were significantly attenuated by MK-467. Most MED effects returned to baseline during step 2 of MK-467 infusion and step 3 of MED infusion (MED/MK-467 ratio 1:18 to 1:50). Plasma concentrations of MED tended to be lower with the addition of MK-467. The use of step infusions helped to narrow down the therapeutic range for the MED/MK-467 infusion dose ratio during isoflurane anaesthesia in dogs.

Comparative persistence of the TNF antagonists in rheumatoid arthritis--a population-based cohort study.

ObjectiveTo compare persistence with tumor necrosis factor alpha (TNF) antagonists among rheumatoid arthritis patients in British Columbia. Treatment persistence has been suggested as a proxy for real-world therapeutic benefit and harm of treatments for chronic non-curable diseases, including rheumatoid arthritis. We hypothesized that the different pharmacological characteristics of infliximab, adalimumab and etanercept cause statistically and clinically significant differences in persistence.MethodsWe conducted a population-based cohort study using administrative health data from the Canadian province of British Columbia. The study cohort included rheumatoid arthritis patients who initiated the first course of a TNF antagonist between 2001 and 2008. Persistence was measured as the time between first dispensing to discontinuation. Drug discontinuation was defined as a drug-free interval of 180 days or switching to another TNF antagonist, anakinra, rituximab or abatacept. Persistence was estimated and compared using survival analysis.ResultsThe study cohort included 2,923 patients, 63% treated with etanercept. Median persistence in years (95% confidence interval) with infliximab was 3.7 (2.9–4.9), with adalimumab 3.3 (2.6–4.1) and with etanercept 3.8 (3.3–4.3). Similar risk of discontinuation was observed for the three drugs: the hazard ratio (95% confidence interval) was 0.98 (0.85–1.13) comparing infliximab with etanercept, 0.95 (0.78–1.15) comparing infliximab with adalimumab and 1.04 (0.88–1.22) comparing adalimumab with etanercept.ConclusionsSimilar persistence was observed with infliximab, adalimumab and etanercept in rheumatoid arthritis patients during the first 9 years of use. If treatment persistence is a good proxy for the therapeutic benefit and harm of these drugs, then this finding suggests that the three drugs share an overall similar benefit-harm profile in rheumatoid arthritis patients.

Biologics in the Treatment of Skin Diseases During Pregnancy and Lactation

Dermatologists are frequently faced with questions about the safety of commonly prescribed topical and systemic medications during pregnancy and lactation. Safety data, particularly regarding medications that are unique to dermatology, can be difficult to find as no unified database or reference guides for clinicians are currently available. In the absence of definitive data, it is prudent to recommend to avoid if possible treatment with biologics during pregnancy. The tumor necrosis factor (TNF)-alpha antagonists and ustekinumab have been labeled pregnancy category B, which allows for their use in pregnant patients with severe psoriasis or psoriatic arthritis. In contrast, rituximab is classified as pregnancy category C (although anecdotal data indicate that rituximab has been used safely in pregnancy as well). Regarding lactation, it has been shown that biologics are secreted into breast milk, but whether they are absorbed by the infant’s gastrointestinal system is unlikely. Although no adverse outcomes have been demonstrated in all case reports available, it may be prudent to advise against breastfeeding while on anti-TNF, ustekinumab, or rituximab therapy until further evidence is collected.

Profiling of the Tox21 10K compound library for agonists and antagonists of the estrogen receptor alpha signaling pathway.

The U.S. Tox21 program has screened a library of approximately 10,000 (10K) environmental chemicals and drugs in three independent runs for estrogen receptor alpha (ERα) agonist and antagonist activity using two types of ER reporter gene cell lines, one with an endogenous full length ERα (ER-luc; BG1 cell line) and the other with a transfected partial receptor consisting of the ligand binding domain (ER-bla; ERα β-lactamase cell line), in a quantitative high-throughput screening (qHTS) format. The ability of the two assays to correctly identify ERα agonists and antagonists was evaluated using a set of 39 reference compounds with known ERα activity. Although both assays demonstrated adequate (i.e. >80%) predictivity, the ER-luc assay was more sensitive and the ER-bla assay more specific. The qHTS assay results were compared with results from previously published ERα binding assay data and showed >80% consistency. Actives identified from both the ER-bla and ER-luc assays were analyzed for structure-activity relationships (SARs) revealing known and potentially novel ERα active structure classes. The results demonstrate the feasibility of qHTS to identify environmental chemicals with the potential to interact with the ERα signaling pathway and the two different assay formats improve the confidence in correctly identifying these chemicals.

Etanercept biosimilars

Etanercept was the first tumour necrosis factor alpha antagonist approved in the USA for the treatment of rheumatoid arthritis, in 1998, and then for other diseases. With the etanercept patent set to expire in the EU in 2015, a number of etanercept copies have reached the production phase and are undergoing clinical trials, with the promise of being cheaper alternatives to the reference product. In a global scenario that is favourable to the entry of biosimilars, this article discusses the stage of development, manufacture, clinical trials and the regulatory process involved in the approval of etanercept biosimilars, compiling the literature data. Reducing treatment cost is the principal attraction for biosimilars to emerge in the global market. It is essential for the doctors’ decision on the prescription of these medications, as well as for payers, to have clearly defined studies of clinical equivalence, quality, and safety in order to better evaluate the various copies of etanercept. The authors discuss the need to harmonize different national regulations and the introduction of effective pharmacosurveillance systems for prompt recognition of adverse effects in copies of biopharmaceuticals that differ from those found in the reference products.

Etanercept exacerbates inflammation and pathology in a rabbit model of active pulmonary tuberculosis.

Treatment of chronic inflammatory diseases with tumor necrosis factor alpha (TNF-α) antagonists has been associated with increased risk of tuberculosis (TB). We examined the usefulness of the rabbit model of active pulmonary TB for studying the impact of the human immune modulatory reagent etanercept on the host immune response. Control of Mycobacterium tuberculosis (Mtb) infection, disease pathology, and the global transcriptional response in Mtb-infected lungs of rabbits were studied. Etanercept treatment exacerbated disease pathology and reduced bacillary control in the lungs, compared with infected untreated animals. Reduced collagen and fibrin deposition in the granulomas was associated with significant downregulation of the collagen metabolism and fibrosis network genes and upregulation of genes in the inflammatory response and cell recruitment networks in the lungs of etanercept treated, compared with untreated rabbits. Our results suggest that targeting the TNF-α signaling pathway disrupts the tissue remodeling process, which is required for the formation and maintenance of well-differentiated granulomas and for control of Mtb growth in the lungs. These results validate the use of the rabbit model for investigating the impact of selected human immune modulatory drugs, such as a TNF-α antagonist, on the host immune response and pathogenesis in TB.

Su1405 The Safety of Biologic Use in the Pregnant IBD Patient: Analysis of Patient Characteristics, Pregnancy and Neonatal Outcomes

Background: TNF alpha inhibitors are being increasingly used in IBD in women of fertile age. Studies to date have been mainly limited to case reports and case series with the largest observational cohort from 50 centres in the US. We aimed to prospectively assess the use of anti TNF treatment during pregnancy in a large European cohort. Methods: This was an observational cohort study addressing a 5 year period between 2008-2013. Female patients with IBD who had undergone anti-TNF treatment during pregnancy were identified using the IBD databases of 2 tertiary referral centres for IBD in Dublin. Patient characteristics including disease activity scores, duration, site and concomitant medications were recorded. Pregnancy outcomes including mode of delivery, miscarriage, ante and postnatal complications, age at conception and need for escalation of IBD treatment during pregnancy were also assessed. Neonatal outcomes including low birth weight, pre-term delivery, NICU stays or perinatal infection and timing of vaccines were also recorded. Data were analysed using t testing, contingency and logistic regression analyses. Results: From an IBD population of over 2,500 patients, 31 individual females who underwent anti -TNF treatment during pregnancy from 2008-2013 were identified with a total of 36 pregnancies. Median disease duration at time of pregnancy was 12 years (IQR 3-17). 85% had Crohn's Disease, 15% Ulcerative Colitis. Median Harvey Bradshaw Index pre-pregnancy was 4.5 (IQR 2-13). Median Mayo score was 1 (IQR 0-3). 57.3% received infliximab, 38% adalimumab, 4.7% certolizimab. 53.8% were on concomitant immunemodulators. The majority of patients stopped biologic treatment at the start of the third trimester. 67% had treatment reinstated in the postpartum period. Median age at conception was 30.5 (IQR 25-35). 19% had previous miscarriages. 92% had successful term pregnancies. 22% required escalation of treatment during pregnancy. 19.3% had a pregnancy complication including emergency section. 16% neonates had a low birth weight with 2 preterm deliveries and one case of NICU stay for meconium ileus. No perinatal infections were reported. 20%mothers breastfed. The majority of mothers delayed live vaccination of their children. Interestingly, there was a significant independent association between disease activity at time of conception and low birthweight (p < 0.01). There was no association between adverse outcomes or neonatal infections and anti-TNF use noted in this cohort.Conclusion: Disease control at time of conception and through pregnancy should be the main goal of treatment in this patient cohort and the use of TNF alpha antagonists to achieve this appears to warranted to improve pregnancy outcomes though definitive safety has yet to be proven.

Su1406 Efficacy, Safety, and Demographics Factor of Adalimumab Therapy in 1693 Japanese Crohn's Disease Patients

Background: TNF alpha inhibitors are being increasingly used in IBD in women of fertile age. Studies to date have been mainly limited to case reports and case series with the largest observational cohort from 50 centres in the US. We aimed to prospectively assess the use of anti TNF treatment during pregnancy in a large European cohort. Methods: This was an observational cohort study addressing a 5 year period between 2008-2013. Female patients with IBD who had undergone anti-TNF treatment during pregnancy were identified using the IBD databases of 2 tertiary referral centres for IBD in Dublin. Patient characteristics including disease activity scores, duration, site and concomitant medications were recorded. Pregnancy outcomes including mode of delivery, miscarriage, ante and postnatal complications, age at conception and need for escalation of IBD treatment during pregnancy were also assessed. Neonatal outcomes including low birth weight, pre-term delivery, NICU stays or perinatal infection and timing of vaccines were also recorded. Data were analysed using t testing, contingency and logistic regression analyses. Results: From an IBD population of over 2,500 patients, 31 individual females who underwent anti -TNF treatment during pregnancy from 2008-2013 were identified with a total of 36 pregnancies. Median disease duration at time of pregnancy was 12 years (IQR 3-17). 85% had Crohn's Disease, 15% Ulcerative Colitis. Median Harvey Bradshaw Index pre-pregnancy was 4.5 (IQR 2-13). Median Mayo score was 1 (IQR 0-3). 57.3% received infliximab, 38% adalimumab, 4.7% certolizimab. 53.8% were on concomitant immunemodulators. The majority of patients stopped biologic treatment at the start of the third trimester. 67% had treatment reinstated in the postpartum period. Median age at conception was 30.5 (IQR 25-35). 19% had previous miscarriages. 92% had successful term pregnancies. 22% required escalation of treatment during pregnancy. 19.3% had a pregnancy complication including emergency section. 16% neonates had a low birth weight with 2 preterm deliveries and one case of NICU stay for meconium ileus. No perinatal infections were reported. 20%mothers breastfed. The majority of mothers delayed live vaccination of their children. Interestingly, there was a significant independent association between disease activity at time of conception and low birthweight (p < 0.01). There was no association between adverse outcomes or neonatal infections and anti-TNF use noted in this cohort.Conclusion: Disease control at time of conception and through pregnancy should be the main goal of treatment in this patient cohort and the use of TNF alpha antagonists to achieve this appears to warranted to improve pregnancy outcomes though definitive safety has yet to be proven.

Negatively regulating TLR4/NF-κB signaling via PPARα in endotoxin-induced uveitis

Toll-like receptor (TLR) signaling plays a fundamental role in the induction and progression of autoimmune disease. In the present study, we showed that lipopolysaccharide (LPS), a TLR4 ligand, functions as an antagonist of peroxisome proliferator-activated receptor alpha (PPARα), a nuclear transcription factor. Using endotoxin induced uveitis (EIU) as a model, we found that TLR was negatively regulated by PPARα. Our data revealed that treatment with the PPARα agonist fenofibrate dramatically prevented LPS-induced uveitis and inhibited TLR/ Nuclear factor-kappaB (NF-κB) signaling during inflammation. Evaluation of the severity of anterior uveitis further showed that PPARα agonist treatment significantly decreased inflammatory cell infiltration, total protein concentration, vessel density, inflammatory cytokine production, and clinical scores in the anterior section of the eye during EIU. Moreover, fenofibrate administration recovered retinal function and decreased the production of inflammatory cytokines, retinal vascular leukostasis, and inflammatory cell infiltration into the posterior section of the eyes during EIU. In vitro studies further showed that down-regulation or deletion of PPARα led to increased TLR4 levels and the activation of NF-κB signaling in RPE cells and also blocked the anti-inflammatory effects of fenofibrate. Furthermore, activation or up-regulation of PPARα decreased TLR4 levels and inhibited the NF-κB signaling pathway induced by LPS in RPE cells. In TLR4-expressing reporter cells, activation or up-regulation of PPARα partially inhibited the activation of NF-κB and also decreased TLR4 transcriptional activity. In conclusion, the activation of PPARα represents a novel therapeutic strategy for human uveitis, as PPARα negatively regulates TLR4 activity and therefore exerts anti-inflammatory actions.