IL-1 Receptor Agonist Research Articles

The role of inflammation in intravenous immune globulin-mediated hemolysis.

Intravenous immune globulin (IVIG) therapy has shown great success in a number of autoimmune and inflammatory conditions and its use continues to increase worldwide. There is growing awareness of significant side effects of high-dose IVIG: however, particularly severe hemolysis in patients that are non-group O. It has been proposed that IVIG-associated hemolysis may be heralded by an existing inflammatory condition. In the work presented herein, we have provided a review of the pathophysiology of inflammation, particularly as it applies in immune-mediated red blood cell hemolysis, and a summary of previous publications that suggest an association between IVIG-mediated hemolysis and a state of existing inflammation. In addition, preliminary results from a prospective study to address the mechanism of IVIG-associated hemolysis are provided. These preliminary data support the idea of an existing inflammatory condition preceding overt hemolysis after high-dose IVIG therapy that: 1) is restricted to non-group O patients, 2) is seen when using IVIG doses of more than 2 g/kg, 3) involves an activated mononuclear phagocyte system, 4) may be presaged by a significant increase in the anti-inflammatory cytokine interleukin-1 receptor agonist, and 5) is independent of secretor status.

Small-sided games training reduces CRP, IL-6 and leptin in sedentary, middle-aged men.

Long-term physical activity is reported to improve chronic systemic inflammation, which provides protection against the ensuing development of chronic disease. Accordingly, the present study assessed changes in pro- and anti-inflammatory cytokines, aerobic capacity and body composition following 8 weeks of either small-sided games (SSG) or cycling (CYC) training compared to a sedentary control (CON) condition. Thirty-three middle-aged, sedentary men were randomized into CYC (n = 11), SSG (n = 11), or CON (n = 11) conditions. The CYC and SSG conditions trained 3 days/week for 8 weeks, whilst CON maintained habitual activity and dietary patterns. Pre- and post-intervention testing included a dual-energy X-ray absorptiometry scan, sub-maximal (80% maximal heart rate) aerobic capacity (VO₂) and fasting venous blood. Venous blood measures for pro-inflammatory markers included C-reactive protein (CRP), interleukin (IL)-6, IL-1β, tumor necrosis factor-α, and leptin; anti-inflammatory markers included IL-10, IL-1 receptor agonist, and adiponectin. Both CYC and SSG increased submaximal power output and VO₂ (P < 0.05), decreased total body fat-mass (TB-FM; P < 0.05), and CRP (SSG, -0.45 ± 0.42 mg L(-1); P = 0.008; CYC, -0.44 ± 0.59 mg L(-1); P = 0.02). Only SSG increased total body fat-free mass (TB-FFM; +1.1 ± 1.2 kg; P = 0.001) and decreased concentration of plasma IL-6 (-0.69 ± 0.62 pg mL(-1); P = 0.002) and leptin (-2,212 ± 2,531 ng mL(-1); P = 0.014). Cycling and SSG training were both effective at improving CRP, VO₂ and TB-FM. Furthermore, SSG training has also shown to be an effective training approach in reducing IL-6 and leptin and increasing muscle mass within sedentary, middle-aged men.

Surgical stress influences cytokine content in autologous conditioned serum.

No recommendations have been made regarding the relative timing of blood collection for autologous conditioned serum (ACS) preparation and surgical procedures. 1) To identify effects of surgical stress on cytokine levels in ACS, 2) identify haematological markers for prediction of cytokine production in ACS and 3) investigate the necessity for specialised ACS containers when preparing a cytokine-rich serum. Experimental in vitro study. Blood was drawn from 15 stallions admitted for elective castration preoperatively and 22-24 h post operatively and incubated in ACS containers and plastic vacutainer tubes containing Z Serum Clot Activator. Concentrations of interleukin (IL)-1 receptor agonist (IL-1Ra), IL-10, IL-1β, tumour necrosis factor (TNF)-α, insulin-like growth factor (IGF)-1 and transforming growth factor (TGF)-β were determined in all serum samples and compared between preparation methods and sampling time by ANOVA. Changes in cytokine levels induced by incubation, defined as delta cytokine, were calculated by subtracting the baseline levels from the levels in incubated samples. Based on post operative serum amyloid A (SAA), horses were grouped into 'mild', moderate' and 'marked' surgical stress; delta cytokine levels in post operative samples were compared between these groups by ANOVA. Delta IGF-1 was significantly lower in post operative samples compared with preoperative. Horses in the 'marked' surgical stress group had significantly lower delta IL-1Ra and delta TGF-β than the 'moderate' group and significantly lower delta IGF-1 than the 'mild' group. No association between cytokine levels and haematology variables were identified. Cytokine levels were comparable between serum prepared in blood tubes and in specialised ACS containers. Surgical stress influences the cytokine content in ACS. Useful predictors of cytokine production in ACS were not identified. Specialised ACS containers may not be necessary for preparation of a cytokine-rich serum.

A randomized trial of an early measles vaccine at 4½ months of age in Guinea-Bissau: sex-differential immunological effects.

BackgroundAfter measles vaccine (MV), all-cause mortality is reduced more than can be explained by the prevention of measles, especially in females.ObjectiveWe aimed to study the biological mechanisms underlying the observed non-specific and sex-differential effects of MV on mortality.MethodsWithin a large randomised trial of MV at 4.5 months of age blood samples were obtained before and six weeks after randomisation to early MV or no early MV. We measured concentrations of cytokines and soluble receptors from plasma (interleukin-1 receptor agonist (IL-1Ra), IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, soluble urokinase-type plasminogen activator receptor), and secreted cytokines (interferon-γ, TNF-α, IL-5, IL-10, IL-13, IL-17) after in vitro challenge with innate agonists and recall antigens. We analysed the effect of MV in multiple imputation regression, overall and stratified by sex. The majority of the infants had previously been enrolled in a randomised trial of neonatal vitamin A. Post hoc we explored the potential effect modification by neonatal vitamin A.ResultsOverall, MV versus no MV was associated with higher plasma MCP-1 levels, but the effect was only significant among females. Additionally, MV was associated with increased plasma IL-1Ra. MV had significantly positive effects on plasma IL-1Ra and IL-8 levels in females, but not in males. These effects were strongest in vitamin A supplemented infants. Vitamin A shifted the effect of MV in a pro-inflammatory direction.ConclusionsIn this explorative study we found indications of sex-differential effects of MV on several of the plasma biomarkers investigated; in particular MV increased levels in females, most strongly in vitamin A recipients. The findings support that sex and micronutrient supplementation should be taken into account when analysing vaccine effects.Trial Registrationclinicaltrials.gov number NCT 00168545

Physico-Chemical Factors Influencing Autologous Conditioned Serum Purification

Autologous conditioned serum (ACS) is a recent biotherapy based on certain cytokines anti-inflammatory properties mainly used for the reduction of osteoarthritis (OA) symptoms. Here we investigated different physico-chemical factors influencing ACS purification and cytokine production. Human venous blood was incubated in the presence of different diameter beads (respectively 2.5, 3, 3.5, and 4 mm) or glass beads with different types of coating (polished or coated with CrSO4). Sera were recovered, and the concentrations of pro-inflammatory and anti-inflammatory relevant cytokines were measured using Luminex® technology. Fresh whole blood incubated for 24 h highly increased production of interleukin (IL)-6 and IL-8 cytokines. At the same time, the concentrations of IL-1β, IL-1 receptor agonist (IL-1Ra), IL-10, and tumor necrosis factor (TNF)-α were slightly induced. The highest cytokine concentrations were obtained with the exposure of whole blood to 3-mm glass beads and 3.5-mm polished beads. The minimum IL-1β/IL-1Ra ratio obtained was 3.2±1.3 after 24-h incubation without any beads. ACS has been shown to alleviate clinical symptoms of OA in clinical studies. This descriptive study demonstrated that different pro- and anti-inflammatory cytokines are present in ACS since no selective anti-inflammatory cytokines were produced based on the different protocols. Furthermore, we showed that CrSO4-treated glass beads are not necessary and that the absence of beads combined with a 24-h incubation could also lead to an enriched serum.

Differences in post-exercise inflammatory and glucose regulatory response between sedentary indigenous Australian and Caucasian men completing a single bout of cycling.

This study compared the acute inflammatory and glucose responses following aerobic exercise in sedentary Indigenous Australian and Caucasian men, matched for fitness and body composition. Sedentary Indigenous (n = 10) and Caucasian (n = 9) Australian men who were free from chronic disease volunteered to participate. Following baseline testing, participants completed a 40 min cycling bout at ∼80% maximal heart rate. Fasting venous blood was collected pre, 0, 30, 60, and 240 min post-exercise for analysis of glucose, insulin, cortisol, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-1 receptor agonist (ra), and C-reactive protein (CRP). Resting TNF-α and glucose concentrations were significantly higher in the Indigenous group (P < 0.05). IL-6 and IL-1ra were elevated for longer in Caucasian (P < 0.05), compared with the Indigenous group (P > 0.05). The post-exercise (0 min) increase in cortisol and glucose for the Caucasians was higher (P < 0.05) than the attenuated responses within the Indigenous group (P > 0.05). Despite being matched for fitness and body composition the Indigenous men had elevated resting TNF-α and glucose compared with the Caucasian men, which may have contributed to the suppressed post-exercise anti-inflammatory response of the Indigenous men; however, glucose normalized between groups post-exercise. As such, it is recommended for acute moderate-intensity exercise to be completed daily for long-term improvements in glucose regulation, irrespective of ancestry. Of note, results suggest it to be even more pertinent for exercise to be encouraged for Indigenous Australian men due to their elevated resting glucose levels at a younger age, when compared to the respective Caucasian group.

Omega‐3 PUFA supplementation and the response to evoked endotoxemia in healthy volunteers

Fish oil-derived n-3 PUFA may improve cardiometabolic health through modulation of innate immunity. However, findings in clinical studies are conflicting. We hypothesized that n-3 PUFA supplementation would dose-dependently reduce the systemic inflammatory response to experimental endotoxemia in healthy humans. The Fenofibrate and omega-3 Fatty Acid Modulation of Endotoxemia (FFAME) study was an 8-wk randomized double-blind trial of placebo or n-3 PUFA supplementation (Lovaza 465 mg eicosapentaenoic acid (EPA) + 375 mg docosahexaenoic acid (DHA)) at "low" (1/day, 900 mg) or "high" (4/day, 3600 mg) dose in healthy individuals (N = 60; age 18-45; BMI 18-30; 43% female; 65% European-, 20% African-, 15% Asian-ancestry) before a low-dose endotoxin challenge (LPS 0.6 ng/kg intravenous bolus). The endotoxemia-induced temperature increase was significantly reduced with high-dose (p = 0.03) but not low-dose EPA + DHA compared to placebo. Although there was no statistically significant impact of EPA + DHA on individual inflammatory responses (tumor necrosis factor-α (TNF-α), IL-6, monocyte chemotactic protein (MCP-1), IL-1 receptor agonist (IL-1RA), IL-10, C-reactive protein (CRP), serum amyloid A (SAA)), there was a pattern of lower responses across all biomarkers with high-dose (nine of nine observed), but not low-dose EPA + DHA. EPA + DHA at 3600 mg/day, but not 900 mg/day, reduced fever and had a pattern of attenuated LPS induction of plasma inflammatory markers during endotoxemia. Clinically and nutritionally relevant long-chain n-3 PUFA regimens may have specific, dose-dependent, anti-inflammatory actions.

Acute Painful Stress and Inflammatory Mediator Production

Background: Proinflammatory pathways may be activated under conditions of painful stress, which is hypothesized to worsen the experience of pain and place medically vulnerable populations at risk for increased morbidity. Objectives: To evaluate the effects of pain and subjective pain-related stress on proinflammatory activity. Methods: A total of 19 healthy control subjects underwent a single standard cold-pressor pain test (CPT) and a no-pain control condition. Indicators of pain and stress were measured and related to inflammatory immune responses [CD8+ cells expressing the integrin molecule CD11a (CD811a), interleukin (IL)-1 receptor agonist (IL-1RA), and IL-6] immediately following the painful stimulus and compared to responses under no-pain conditions. Heart rate and mean arterial pressure were measured as indicators of sympathetic stimulation. Results: CPT was clearly painful and generated an activation of the sympathetic nervous system. CD811a increased in both conditions, but with no statistically significantly greater increase following CPT (p < 0.06). IL-1RA demonstrated a non-statistically significant increase following CPT (p < 0.07). The change in IL-6 following CPT differed significantly from the response seen in the control condition (p < 0.02). Conclusions: These findings suggest that CP acute pain may affect proinflammatory pathways, possibly through mechanisms related to adrenergic activation.

Gingival fibroblast responsiveness is differentially affected by Porphyromonas gingivalis: implications for the pathogenesis of periodontitis

In periodontitis, tissue damage results mainly from aberrant host responses to oral microorganisms. Fibroblasts can play an important role in this. Gingival fibroblasts do not develop tolerance against the lipopolysaccharide of Porphyromonas gingivalis, a keystone pathogen in periodontitis, which may partly explain the persistence of inflammation. However, besides lipopolysaccharide, live P. gingivalis possess numerous virulence traits to impair host-responses. We hypothesized that fibroblast-responsiveness to a bacterial challenge could be affected by live P. gingivalis. We investigated if inflammatory responses of gingival fibroblasts to P. gingivalis were altered, when the fibroblasts had encountered P. gingivalis previously. On consecutive days, primary human gingival fibroblasts were challenged twice for 6 h with live P. gingivalis, or fibroblasts were preincubated for 24 h with a lower concentration of live P. gingivalis and re-challenged for 6 h with a higher concentration. As the P. gingivalis capsule and proteases are involved in modulating host responses, we used encapsulated P. gingivalis W83 and a non-encapsulated mutant, and P. gingivalis ATCC33277 and a lys-gingipain and arg-gingipain mutant, to challenge fibroblasts. With all P. gingivalis-strains, interleukin-8 and monocyte chemoattractant protein-1 responses to the second challenge were less strong in fibroblasts that had been challenged with P. gingivalis before. These lower responses might correspond with higher interleukin-1 receptor agonist expression. Fibroblast responses to a second challenge were not influenced by 24 h preincubation. Reduced chemokine responses after consecutive potent P. gingivalis challenges indicate that gingival fibroblast responsiveness is affected by a previous bacterial encounter. In periodontitis, such reduced chemokine responses may impair chemotaxis and clearance of oral microorganisms, thereby leading to prolonged inflammatory responses and tissue damage.

Identification of novel interleukin 1 beta family genes in Japanese flounder Paralichthys olivaceus

Gene in the interleukin 1 family plays a central role in the regulation of immune and inflammatory responses. Here, we describe two novel IL-1-like gene in Japanese flounder Paralichthys olivaceus (jfIL1-L1 and jfIL1-L2). jfIL1β-L1 was homologous to Nile Tilapia IL-1β-like gene and Arctic char IL-1, and jfIL1β-L2 showed homology to hypothetical protein LOC100699119 of Nile Tilapia and rainbow trout Oncorhynchus mykiss IL-1 receptor agonist (RA). The deduced amino acids sequences of these IL-1β-like genes showed very low identities to the Japanese flounder IL-1 (jfIL-1). Phylogenetic analysis confirmed that jfIL1β-L1 and -L2 were distinct from jfIL-1. The gene encoding the predicted ORF of jfIL1β-L1 and -L2 is divided into 6 exons and 7 exons, respectively. Transcripts of jfIL1β-L1 were detected in gills, intestine, kidney and spleen, and those of jfIL1β-L2 were detected in gills, intestine and spleen. The mRNA levels of jfIL1β-L1 and -L2 were not effect or slightly decreased by treatment with LPS and the formalin-killed cells of Edwardsiella tarda whilst mRNA levels of jfIL1β were significantly increased in the kidney and spleen at 6 h by these treatments.

Inflammasome-dependent pyroptosis and IL-18 protect against Burkholderia pseudomallei lung infection while IL-1β is deleterious.

Burkholderia pseudomallei is a Gram-negative bacterium that infects macrophages and other cell types and causes melioidosis. The interaction of B. pseudomallei with the inflammasome and the role of pyroptosis, IL-1β, and IL-18 during melioidosis have not been investigated in detail. Here we show that the Nod-like receptors (NLR) NLRP3 and NLRC4 differentially regulate pyroptosis and production of IL-1β and IL-18 and are critical for inflammasome-mediated resistance to melioidosis. In vitro production of IL-1β by macrophages or dendritic cells infected with B. pseudomallei was dependent on NLRC4 and NLRP3 while pyroptosis required only NLRC4. Mice deficient in the inflammasome components ASC, caspase-1, NLRC4, and NLRP3, were dramatically more susceptible to lung infection with B. pseudomallei than WT mice. The heightened susceptibility of Nlrp3-/- mice was due to decreased production of IL-18 and IL-1β. In contrast, Nlrc4-/- mice produced IL-1β and IL-18 in higher amount than WT mice and their high susceptibility was due to decreased pyroptosis and consequently higher bacterial burdens. Analyses of IL-18-deficient mice revealed that IL-18 is essential for survival primarily because of its ability to induce IFNγ production. In contrast, studies using IL-1RI-deficient mice or WT mice treated with either IL-1β or IL-1 receptor agonist revealed that IL-1β has deleterious effects during melioidosis. The detrimental role of IL-1β appeared to be due, in part, to excessive recruitment of neutrophils to the lung. Because neutrophils do not express NLRC4 and therefore fail to undergo pyroptosis, they may be permissive to B. pseudomallei intracellular growth. Administration of neutrophil-recruitment inhibitors IL-1ra or the CXCR2 neutrophil chemokine receptor antagonist antileukinate protected Nlrc4-/- mice from lethal doses of B. pseudomallei and decreased systemic dissemination of bacteria. Thus, the NLRP3 and NLRC4 inflammasomes have non-redundant protective roles in melioidosis: NLRC4 regulates pyroptosis while NLRP3 regulates production of protective IL-18 and deleterious IL-1β.

Acute mountain sickness, inflammation, and permeability: new insights from a blood biomarker study

The pathophysiology of acute mountain sickness (AMS) is unknown. One hypothesis is that hypoxia induces biochemical changes that disrupt the blood-brain barrier (BBB) and, subsequently, lead to the development of cerebral edema and the defining symptoms of AMS. This study explores the relationship between AMS and biomarkers thought to protect against or contribute to BBB disruption. Twenty healthy volunteers participated in a series of hypobaric hypoxia trials distinguished by pretreatment with placebo, acetazolamide (250 mg), or dexamethasone (4 mg), administered using a randomized, double-blind, placebo-controlled, crossover design. Each trial included peripheral blood sampling and AMS assessment before (-15 and 0 h) and during (0.5, 4, and 9 h) a 10-h hypoxic exposure (barometric pressure = 425 mmHg). Anti-inflammatory and/or anti-permeability [interleukin (IL)-1 receptor agonist (IL-1RA), heat shock protein (HSP)-70, and adrenomedullin], proinflammatory (IL-6, IL-8, IL-2, IL-1β, and substance P), angiogenic, or chemotactic biomarkers (macrophage inflammatory protein-1β, VEGF, TNF-α, monocyte chemotactic protein-1, and matrix metalloproteinase-9) were assessed. AMS-resistant subjects had higher IL-1RA (4 and 9 h and overall), HSP-70 (0 h and overall), and adrenomedullin (overall) compared with AMS-susceptible subjects. Acetazolamide raised IL-1RA and HSP-70 compared with placebo in AMS-susceptible subjects. Dexamethasone also increased HSP-70 and adrenomedullin in AMS-susceptible subjects. Macrophage inflammatory protein-1β was higher in AMS-susceptible than AMS-resistant subjects after 4 h of hypoxia; dexamethasone minimized this difference. Other biomarkers were unrelated to AMS. Resistance to AMS was accompanied by a marked anti-inflammatory and/or anti-permeability response that may have prevented downstream pathophysiological events leading to AMS. Conversely, AMS susceptibility does not appear to be related to an exaggerated inflammatory response.

Mortality in Patients With Septic Shock Correlates With Anti-Inflammatory But not Proinflammatory Immunomodulatory Molecules

Mortality in patients with septic shock remains unacceptably high and the attempts to antagonize certain proinflammatory cytokines based on the results of animal model studies have failed to improve survival rates. The objective of this article is to examine the pro-/anti-inflammatory cytokine balance in patients with septic shock and its connection with mortality. Serum levels of proinflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin 1β [IL-1β], interferonγ [IFN-γ], and IL-6) and soluble cytokine antagonists (soluble TNF receptor I [sTNF-RI], sTNF-RII, and IL-1Ra) were determined on admission to the intensive care unit (ICU) and 3, 7, 14, and 28 days later in 52 patients with septic shock and in 36 healthy controls. Specific sandwich enzyme-linked immunosorbent assay (ELISA) was used for all determinations. Serum levels of most of the pro- and anti-inflammatory molecules examined (TNF-α, IL-6, sTNF-RI, sTNF-RII, and IL-1 receptor agonist [IL-1Ra]) were significantly elevated on admission and during the 28-day observation period in patients when compared to controls. Notably, the anti-inflammatory mediators sTNF-RI, sTNF-RII, and IL-1Ra were better predictors of mortality. Receiver-operating characteristic (ROC) analysis revealed that sTNF-RI or sTNF-RII concentrations over 2767 or 4619 pg/mL, respectively, determined a high risk of death (sensitivity: 100%-100%, specificity: 57.1%-71.4%, area under the curve [AUC] 0.759-0.841, respectively), whereas IL-1Ra concentrations below 7033 pg/mL determined a high probability of survival (sensitivity: 60%, specificity: 100%, AUC 0.724). In addition, IFN-γ levels were significantly higher in survivors than in controls during the initial 2 weeks of observation. Our data show that serum cytokine disturbance patterns have prognostic significance in patients with septic shock admitted to the ICU. The pattern, defined by an early response to continuously elevated anti-inflammatory cytokine serum levels, is associated with an enhanced risk of a fatal outcome for patients.

Circulating Levels of 8 Cytokines and Marine n-3 Fatty Acids and Indices of Obesity in Japanese, White, and Japanese American Middle-Aged Men

This study examines the differences in circulating levels of cytokines among Japanese in Japan (JJ), Japanese Americans (JA), and whites and their associations with obesity and marine n-3 fatty acids (FA) in a cross-sectional population-based study of 297 men aged 40-49 (100 JJ, 99 whites, and 98 JA). Experimental studies show that cytokines are associated with obesity positively and marine n-3 FA inversely. Serum interleukin-1alpha (IL-1alpha), IL-1 receptor agonist (IL-1ra), IL-4, IL-8, IL-10, inducible protein-10 (IP-10), tumor necrosis factor-alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1), and marine n-3 FA were determined. Body mass index (BMI), waist circumference, and computed tomography-measured visceral and subcutaneous adipose tissues were determined. The JJ had significantly lower levels of IL-1alpha, IL-4, IL-8, MCP-1, and TNF-alpha than whites and JA. Whites and JA had similar levels of IL-1alpha, IL-4, and IL-8 whereas whites had significantly higher levels of MCP-1 and TNF-alpha than JA. The JJ were least obese (BMI (kg/m(2)), mean +/- standard deviation) 23.6 +/- 2.8, 27.9 +/- 4.6, and 27.9 +/- 4.5 for JJ, whites, and JA, respectively. The JJ had marine n-3 FA about 100% higher than whites and JA (serum marine n-3 FA (%), median (interquartile range) 8.79 (7.41, 11.16), 3.47 (2.63, 4.83), and 4.44 (3.33, 6.01) for JJ, whites, and JA, respectively). Generally cytokines had weak and nonsignificant associations with indices of obesity and nonsignificant associations with marine n-3 FA. BMI had significant inverse associations with IL-1alpha, IL-4, and IL-8 in JA (P < 0.05). Marine n-3 FA had marginally significant inverse associations with IL-8 in JJ (P = 0.055) and TNF-alpha in whites (P = 0.076). The JJ had lower levels of many cytokines than whites and JA. Generally cytokines had weak and nonsignificant associations with indices of obesity and marine n-3 FA. Further investigation is needed to determine why JJ had lower circulating levels of cytokines.

Mesenchymal stem cells in arthritis: role of bone marrow microenvironment

Based on their capacity to suppress immune responses, multipotent mesenchymal stromal cells (MSCs) are intensively studied for regenerative medicine. Moreover, MSCs are potent immunomodulatory cells that occur through the secretion of soluble mediators including nitric oxide, transforming growth factor beta, and HLAG5. The MSCs, however, are also able to express inflammatory mediators such as prostaglandin E2 or IL-6. MSCs in the bone marrow are in close contact with T cells and B cells, and they regulate immunological memory by organizing defined numbers of dedicated survival niches for plasma cells and memory T cells in the bone marrow. The role of MSCs in arthritis remains controversial - in some studies, murine allogeneic MSCs are able to decrease arthritis; in other studies, MSCs worsen the local inflammation. A recent paper in Arthritis Research and Therapy shows that bone marrow MSCs have decreased osteoblastic potential in rheumatoid arthritis, which may be related to chronic inflammation or to loss of expression of IL-1 receptor agonist. That article raises the importance of the bone marrow microenvironment for MSC biology.

Are genetic variants of Caspase-1 and Cryopyrin associated with systemic JIA?

Background The systemic subtype of juvenile idiopathic arthritis (sJIA) can be the most severe, and unlike other forms of JIA is an autoinflammatory disease. There is evidence for the involvement of IL-1 in sJIA: treatment with the IL-1 receptor agonist, Anakinra, has shown dramatic improvement in some sJIA patients. Additionally we have shown a significant association with members of the IL-1 gene family and sJIA [1]. Caspase-1 is required to cleave IL-1β into its active form and Cryopyrin (NLRP3) is part if the IL-1β inflammasome, required for the activation of caspase-1. Mutations in NLRP3 have been found in patients that have similar clinical features with sJIA, e.g. CINCA. Here we describe a candidate gene association study of CASP1 and NLRP3 in sJIA.

β-Glucan, Immune Function, and Upper Respiratory Tract Infections in Athletes

This study investigated the effects of oat beta-glucan (BG) supplementation on chronic resting immunity, exercise-induced changes in immune function, and self-reported upper respiratory tract infection (URTI) incidence in human endurance athletes. Trained male cyclists were randomized to BG (N = 19) or placebo (P; N = 17) groups and under double-blind procedures received BG (5.6 g x d(-1)) or P beverage supplements for 2 wk before, during, and 1 d after a 3-d period in which subjects cycled for 3 h x d(-1) at approximately 57% maximal watts. URTI symptoms were monitored during BG supplementation and for 2 wk afterward. Blood samples were collected before and after 2 wk of supplementation (both samples, 8:00 a.m.), immediately after the 3-h exercise bout on day 3 (6:00 p.m.), and 14 h after exercise (8:00 a.m.) and were assayed for natural killer cell activity (NKCA), polymorphonuclear respiratory burst activity (PMN-RBA), phytohemagglutinin-stimulated lymphocyte proliferation (PHA-LP), plasma interleukin 6 (IL-6), IL-10, IL-1 receptor agonist (IL-1ra), and IL-8, and blood leukocyte IL-10, IL-8, and IL-1ra mRNA expression. Chronic resting levels and exercise-induced changes in NKCA, PMN-RBA, PHA-LP, plasma cytokines, and blood leukocyte cytokine mRNA did not differ significantly between BG and P groups. URTI incidence during the 2-wk postexercise period did not differ significantly between groups. An 18-d period of BG versus P ingestion did not alter chronic resting or exercise-induced changes in immune function or URTI incidence in cyclists during the 2-wk period after an intensified exercise.

Systemic Expression of Cytokine Production in Patients with Severe Pneumococcal Pneumonia: Effects of Treatment with a β-Lactam versus a Fluoroquinolone

Bacterial alveolar invasion is followed by an inflammatory response. A systemic extension of the compartmentalized immune response has been described in patients with severe pneumonia. The data suggest that some antimicrobials may induce a differential release of cytokines. We conducted a prospective, randomized study in adult patients with severe pneumococcal pneumonia to measure the effects of ceftriaxone and levofloxacin in the systemic cytokine expression over time. Demographic, clinical characteristics, and severity scores were recorded. The serum concentrations of tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, IL-8, IL-10, and IL-1 receptor agonist were measured at 0, 24, 72, and 120 h. A total of 32 patients were included in the study. Both groups were homogeneous in terms of age, comorbidities, severity of disease, and corticosteroid or statin use. With the single exception of IL-1beta, all cytokines were detected in venous blood. All of the cytokines studied showed a similar pattern of progressive decrease over time. No significant differences in the concentrations of any of the cytokines studied were found, with the exception of TNF-alpha, for which lower concentrations were obtained at 120 h in the levofloxacin group (P = 0.014). Basal oxygen saturation (P = 0.034) and heart rate (P = 0.029) returned to normal values earlier in the levofloxacin arm. We demonstrated that in patients with severe pneumococcal pneumonia pro- and anti-inflammatory responses could be detected in venous blood, representing a systemic extension of the compartmentalized response. Treatment with a beta-lactam agent or a fluoroquinolone has different effects on cytokine production and its systemic expression, impacting the clinical course of the disease.

Effect of enalapril and losartan on cytokines in patients with stable angina pectoris awaiting coronary artery bypass grafting and their interaction with polymorphisms in the interleukin-6 gene

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may have anti-inflammatory actions, an effect that could explain some of their beneficial effects on cardiovascular events in clinical trials. Coronary artery bypass grafting (CABG) is associated with a systemic inflammatory response and provides a convenient model to examine the effects of such agents. Genetic polymorphisms may be important in influencing the expression of cytokines, such as interleukin-6 (IL-6). We randomized men awaiting CABG to treatment with enalapril, losartan, or control for 2 months before surgery. Systemic IL-6, IL-8, IL-10, and IL-1 receptor agonists were measured before and after surgery, and genotypes for the -174 G/C and -572 G/C IL-6 gene polymorphisms were determined. Total release of the IL-1 receptor agonist was decreased 29% by enalapril and 31% by losartan (adjusted p = 0.041). IL-6 was decreased 17% by enalapril and 20% by losartan. Subjects possessing the -174 GG genotype produced 20% more IL-6 (adjusted p = 0.029). In these high producers of IL-6, release of IL-6 was decreased 51% by enalapril (adjusted p = 0.001) and 32% by losartan (adjusted p = 0.068). Release of IL-10 was nonsignificantly decreased 26% by enalapril and 21% by losartan, whereas IL-8 was not detected. In conclusion, enalapril and losartan significantly decreased release of the IL-1 receptor agonist after CABG. Enalapril produced a highly significant decrease of 51% in the release of IL-6 in patients identified as high producers of IL-6 by the -174 G/C polymorphism, whereas losartan has a similar but less marked effect. The production of IL-6 in this setting is influenced by the -174 G/C polymorphism.

Remittive agents in pediatric rheumatology.

Children with rheumatic diseases frequently require therapy with disease-modifying antirheumatic drugs and/or biologic agents. Therapies that have been prospectively tested in adults are often used in children before full evaluation of their safety and efficacy. Published experience that may report "off-label" usage can be helpful in decision making, although such reports do not reduce the need for prospective clinical trials in children. The purpose of this review is to summarize the recent published evidence regarding efficacy (and safety, when available) of standard and novel agents used in pediatric rheumatic disease. Etanercept, one of three currently available tumor necrosis factor-alpha inhibitors has a juvenile idiopathic arthritis indication. Novel "off-label" uses in children for interleukin-1 receptor agonist (Anakinra), antiinterleukin-6 receptor antibody (MRA), and rituximab (anti-CD20 monoclonal antibody) are discussed. This review summarizes the published evidence that supports the use of selected disease-modifying antirheumatic drugs and novel biologic agents in children with rheumatic diseases.