Change In IL-1ra Research Articles

Affective neural circuits and inflammatory markers linked to depression and anxiety symptoms in patients with comorbid obesity

Although we have effective treatments for depression and anxiety, we lack mechanistic understanding or evidence-based strategies to tailor these treatments in the context of major comorbidities such as obesity. The current feasibility study uses functional neuroimaging and biospecimen data to determine if changes in inflammatory markers, fecal short-chain fatty acids, and neural circuit-based targets can predict depression and anxiety outcomes among participants with comorbid obesity. Blood and stool samples and functional magnetic resonance imaging data were obtained at baseline and 2 months, during the parent ENGAGE-2 trial. From 30 participants with both biospecimen and fMRI data, this subsample study explored the relationship among changes in inflammatory markers and fecal short-chain fatty acids and changes in neural targets, and their joint relationship with depression and anxiety symptoms. Bivariate and partial correlation, canonical correlation, and partial least squares analyses were conducted, with adjustments for age, sex, and treatment group. Initial correlation analyses revealed three inflammatory markers (IL-1RA, IL-6, and TNF-α) and five neural targets (in Negative Affect, Positive Affect, and Default Mode Circuits) with significantly associated changes at 2 months. Partial least squares analyses then showed that changes in IL-1RA and TNF-α and changes in three neural targets (in Negative Affect and Positive Affect Circuits) at 2 months were associated with changes in depression and anxiety symptoms at 6 months. This study sheds light on the plausibility of incorporation of inflammatory and gastrointestinal biomarkers with neural targets as predictors of depression and comorbid anxiety outcomes among patients with obesity.

Bioactive substances in the stratum corneum of the epidermis found as indicators of skin damage due to sun exposure.

Background/PurposeAlthough an inflammatory response upon acute injury caused by ultraviolet radiation (UV) can be observed immediately, the influence of long‐term, repetitive low‐dose UV exposure on the skin cannot be precisely perceived, making early detection of chronic damage difficult. This study investigated bioactive substances in the stratum corneum as a potential early and sensitive indicator of the influence of sun exposure on the skin using receiver operating characteristic (ROC) analysis.MethodsReceiver operating characteristic analysis was performed to assess the responsiveness of cytokines [interleukin (IL)‐1α, IL‐1 receptor antagonist (IL‐1ra), IL‐10, tumor necrosis factor (TNF)‐α], BCL2‐associated protein X (Bax), Toll‐like receptor (TLR)3, and TLR4 in the stratum corneum of healthy people exposed (dorsum of the hand) and unexposed (inner arm) to UV. Sunscreen was applied to patients with photodermatosis for 4 weeks to evaluate changes in IL‐1ra/IL‐1α, TNF‐α, Bax, and TLR3 levels after sunscreen application, as these molecules exhibited high responsiveness to sun exposure according to ROC analysis. In addition, IL‐1ra, IL‐1α, and IL‐10 levels were quantified by enzyme‐linked immunosorbent assay, and TNF‐α, Bax, TLR3, and TLR4 levels were semi‐quantitatively assessed by immunocytochemistry.ResultsReceiver operating characteristic analysis identified IL‐1ra/IL‐1α, TNF‐α, Bax, and TLR3 in the stratum corneum as highly responsive to sun exposure. Moreover, in participants, including patients with photodermatosis, IL‐1ra/IL‐1α, TNF‐α, and Bax levels decreased significantly after sunscreen application.ConclusionThe results revealed that IL‐1ra/IL‐1α, TNF‐α, and Bax in the stratum corneum represent sensitive indicators of the influence of sun exposure on the skin.

Effects of an intensive lifestyle intervention on the underlying mechanisms of improved glycaemic control in individuals with type 2 diabetes: a secondary analysis of a randomised clinical trial.

The aim was to investigate whether an intensive lifestyle intervention, with high volumes of exercise, improves beta cell function and to explore the role of low-grade inflammation and body weight. This was a randomised, assessor-blinded, controlled trial. Ninety-eight individuals with type 2 diabetes (duration <10years), BMI of 25-40kg/m2, no use of insulin and taking fewer than three glucose-lowering medications were randomised (2:1) to either the standard care plus intensive lifestyle group or the standard care alone group. Standard care consisted of individual guidance on disease management, lifestyle advice and blinded regulation of medication following a pre-specified algorithm. The intensive lifestyle intervention consisted of aerobic exercise sessions that took place 5-6 times per week, combined with resistance exercise sessions 2-3 times per week, with a concomitant dietary intervention aiming for a BMI of 25kg/m2. In this secondary analysis beta cell function was assessed from the 2h OGTT-derived disposition index, which is defined as the product of the Matsuda and the insulinogenic indices. At baseline, individuals were 54.8years (SD 8.9), 47% women, type 2 diabetes duration 5years (IQR 3-8) and HbA1c was 49.3mmol/mol (SD 9.2); 6.7% (SD 0.8). The intensive lifestyle group showed 40% greater improvement in the disposition index compared with the standard care group (ratio of geometric mean change [RGM] 1.40 [95% CI 1.01, 1.94]) from baseline to 12months' follow-up. Plasma concentration of IL-1 receptor antagonist (IL-1ra) decreased 30% more in the intensive lifestyle group compared with the standard care group (RGM 0.70 [95% CI 0.58, 0.85]). Statistical single mediation analysis estimated that the intervention effect on the change in IL-1ra and the change in body weight explained to a similar extent (59%) the variance in the intervention effect on the disposition index. Our findings show that incorporating an intensive lifestyle intervention, with high volumes of exercise, in individuals with type 2 diabetes has the potential to improve beta cell function, associated with a decrease in low-grade inflammation and/or body weight. ClinicalTrials.gov NCT02417012 Graphical abstract.

Relationships Of Serum And Plasma BDNF To TNF-a, IL-10, And IL-1ra During Aerobic Exercise

PURPOSE: To examine the relationship of Brain Derived Neurotrophic Factor (BDNF) in serum and plasma to serum TNF-α, IL-10, and IL-1ra in response to aerobic exercise. METHODS: Six recreationally active men (26.0 ± 2.6 yrs, 180.3 ± 5.3 cm, 85.3 ± 7.6 kg, 48.64 ± 5.2 mL·kg-1·min-1) completed three exercise trials under different conditions: low temperature (5°C), moderate temperature (22°C), and high temperature (35°C). Each protocol consisted of a 60-min cycling trial at 60% VO2max, a 15-min rest, and a time-to-exhaustion trial at 90% VO2max (TTE). Blood was sampled before (PRE) and after the 60-min time trial (60), immediately following the TTE (90), and one hr post-TTE (REC). Serum concentrations of TNF-α, IL-10, IL-1ra, BDNF(-S), and plasma concentrations of BDNF(-P) were analyzed via ELISA. Data were combined across different conditions and analyzed by calculating change scores between PRE and other time points – presented as 60, 90, REC. Relationships between analytes were determined using Pearson Product Moment Correlations, with α ≤ 0.05. Correlation coefficients were described as weak (r: 0.30 – 0.49), moderate (r: 0.50 – 0.69), or strong (r: 0.70 – 0.89). RESULTS: Correlation coefficients between changes in BDNF-S and changes in IL-1ra indicated moderate to strong positive relationships between BDNF-S at 60 with IL-1ra at 60 and 90, BDNF-S at 90 with IL-1ra at 90, and BDNF-S at REC with IL-1ra at 90 and REC (r ≥ 0.568, p ≤ 0.043). Correlation coefficients between BDNF-P and TNF-α indicated a moderate positive relationship between BDNF-P at 60 with TNF-α at 90 (r = 0.513, p = 0.035). Changes in BDNF-S and IL-1ra demonstrated weak to moderate, non-significant correlation coefficients between BDNF-S at 90 and REC with IL-1ra at 60 (r = 0.456, p = 0.087; r = 0.508, p = 0.064; respectively). Similarly, correlation coefficients between changes in BDNF-S and IL-10 presented weak to moderate, non-significant relationships BDNF at 60 and 90 with IL-10 at 60 (r = 0.544, p = 0.068; r = 0.498, p = 0.070; respectively). No other relationships were observed. CONCLUSION: There appears to be a strong relationship between BDNF-S and IL-1ra throughout the trial, suggesting BDNF may be linked to the anti-inflammatory cascade, though not corroborated in BDNF-P.

Elevated concentrations of circulating cytokines and correlations with nerve conduction velocity in human peripheral nerves.

The purpose of the current study was to quantify the potential relationship between various cytokines and peripheral nerve function in humans, in-vivo. Measures of nerve conduction velocity (NCV) were examined prior to and following the induction of a cytokine spike. A significant negative correlation was found between the change in IL-1ra and the change in NCV at 24h post-exercise (r=-0.65, p=0.02) while a significant positive correlation was found between the change in IL-6 and the change in NCV at 2h post-exercise (r=0.61, p=0.048). It may be possible that different cytokines induce a unique neural influence at elevated concentrations.

Biophysical Characterization of Structural Properties and Folding of Interleukin-1 Receptor Antagonist

Structural properties and folding of interleukin-1 receptor antagonist (IL-1ra), a therapeutically important cytokine with a symmetric β-trefoil topology, are characterized using optical spectroscopy, high-resolution NMR, and size-exclusion chromatography. Spectral contributions of two tryptophan residues, Trp17 and Trp120, present in the wild-type protein, have been determined from mutational analysis. Trp17 dominates the emission spectrum of IL-1ra, while Trp120 is quenched presumably by the nearby cysteine residues in both folded and unfolded states. The same Trp17 gives rise to two characteristic negative peaks in the aromatic CD. Urea denaturation of the wild-type protein is probed by measuring intrinsic and extrinsic (binding of 1-anilinonaphthalene-8-sulfonic acid) fluorescence, near- and far-UV CD, and 1D and 2D ( 1H– 15N heteronuclear single quantum coherence (HSQC)) NMR. Overall, the data suggest an essentially two-state equilibrium denaturation mechanism with small, but detectable structural changes within the pretransition region. The majority of the 1H– 15N HSQC cross-peaks of the folded state show only a limited chemical shift change as a function of the denaturant concentration. However, the amide cross-peak of Leu31 demonstrates a significant urea dependence that can be fitted to a two-state binding model with a dissociation constant of 0.95 ± 0.04 M. This interaction has at least a five times higher affinity than reported values for nonspecific urea binding to denatured proteins and peptides, suggesting that the structural context around Leu31 stabilizes the protein–urea interaction. A possible role of denaturant binding in inducing the pretransition changes in IL-1ra is discussed. Urea unfolding of wild-type IL-1ra is sufficiently slow to enable HPLC separation of folded and unfolded states. Quantitative size-exclusion chromatography has provided a hydrodynamic view of the kinetic denaturation process. Thermodynamic stability and unfolding kinetics of IL-1ra resemble those of structurally and evolutionary close IL-1β, suggesting similarity of their free energy landscapes.

Different effects of raloxifene and estrogen on interleukin-1β and interleukin-1 receptor antagonist production using in vitro and ex vivo studies

The increase in lumbar spine BMD in response to Raloxifene (RLX), a selective estrogen receptor modulator, is smaller in magnitude compared to the response to treatment with estradiol (E 2). The reasons for this observation are unclear. Estrogen has a potent effect on the production of proinflammatory cytokines which support osteoclastogenic and bone resorption. Therefore the different response to RLX may relate, at least in part, to a difference in the ability of RLX to modulate the production of proinflammatory cytokines which are abundant in the red marrow of the vertebrae. The aim of this study was to determine the effect of RLX and E 2 both in vitro and ex vivo on the production of the pro-resorptive cytokine interleukin-1β (IL-1β) and its antagonist, interleukin-1receptor antagonist (IL-1ra). We obtained samples of peripheral blood from (a) 10 untreated postmenopausal women with osteopenia (ages 53 to 72 years, mean 61 years), (b) 15 postmenopausal women (ages 52 to 72 years, mean 63 years) at baseline and after 6 months of RLX therapy (60 mg/day) and (c) 10 postmenopausal women (ages 60 to 75 years, mean 64 years) at baseline and 6 months after a single E 2 implant (25 mg). Cultures of whole blood from the untreated women were incubated with RLX or 17β-E 2 at 1 pM, 100 pM, 10 nM and 1 μM concentrations. LPS-stimulated whole blood cultures from the raloxifene- and estradiol-treated women were prepared at baseline and at 6 months. IL-1β and IL-1ra were measured by ELISA in the conditioned media. In vitro there was a significant dose-dependent decrease in IL-1β and IL-1ra in response to 17β-E 2 (both P < 0.0001) which was not apparent in response to RLX (both P > 0.05). In ex vivo cultures from women receiving 6 months treatment with E 2 implants, there was a significant decrease in IL-1β (− 36 ± 8%, P = 0.01) but no significant change in IL-1ra (+ 29 ± 20%, P = 0.3). There was no significant change in either IL-1β or IL-1ra after 6 months RLX therapy (+ 20 ± 14% and + 12 ± 10%, both P > 0.05). We conclude that treatment with RLX, unlike estradiol does not modulate the production of the proinflammatory cytokines IL-1β and IL-1ra using in vitro or ex vivo whole blood culture methods. This may account, at least in part for the reduced efficacy of RLX therapy compared to estrogen which has been observed in vivo on bone mineral density, bone turnover and reduction in fracture risk.

Clinical Response Is Associated with Elevated Plasma Interleukin-1 Receptor Antagonist During Selective Granulocyte and Monocyte Apheresis in Patients with Ulcerative Colitis

Depletion of granulocytes and monocytes (GM) by selective apheresis (GMA) with an Adacolumn exerts an anti-inflammatory effect in patients with ulcerative colitis (UC) or rheumatoid arthritis. However, the mechanism of the anti-inflammatory effect of GMA is not fully understood yet. We investigated the effect of GMA on the plasma concentration of interleukin-1 receptor antagonist (IL-1ra), a potent anti-inflammatory cytokine. Twenty-six patients with active UC received GMA at one session per week for 5 consecutive weeks. Clinical response was defined as Deltaclinical activity index (DeltaCAI=CAI at entry - CAI at post)>or=4, while clinical remission was defined as CAI<or=4. Twenty-one of twenty-six patients (80.8%) responded to GMA. In the first session, plasma from responder patients showed a significant (P < 0.01) increase in IL-1ra in the Adacolumn outflow. In contrast, there was no change in IL-1ra in nonresponders. In conclusion, release of IL-1ra during GMA might be one mechanism of clinical efficacy associated with this therapy.

Inhalation of swine-house dust increases the concentrations of interleukin-1 beta (IL-1β) and interleukin-1 receptor antagonist (IL-1ra) in peripheral blood

Inhalation of dust in swine confinement buildings causes airway inflammation and systemic symptoms. The proinflammatory cytokines interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) increase in bronchoalveolar and nasal lavage fluid, and in serum. The aim of this investigation was to study changes in the IL-1 family of cytokines in peripheral blood in 36 healthy volunteers exposed to swine house dust for 3 h. Interleukin (IL-1β) was measured in platelet poor plasma and in a mononuclear cell fraction (PBMC) and interleukin-1 receptor antagonist (IL-1ra), IL-6 and TNF-α were measured in serum 4 and 7 h after the start of 3 h exposure. Lung function and a methacholine bronchial provocation test were performed before and 7 h after the start of exposure. The leukocyte count in whole blood and the mononuclear cell count in PBMC were examined before, and 4 and 7 h after the start of exposure. The concentration of airborne inhalable dust and endotoxin were measured using personal samples. The concentration of inhalable dust was 23 (20–30) mg m −3 (median 25th–75th percentile) endotoxin was 1·1 (0·8–1·4) μg m −3 and respirable dust ( n=8) was 1·0 (0·7–1·2) mg m −3. IL-1β increased from <0·125 to 0·9 (0·5–1·3) ng l −1 in plasma and from 1·6 to 2·7 (1·1–4·4) ng l −1 in PBMC ( P<0·01). IL-1ra, IL-6 and TNF-α increased 2-, 12- and 2-fold in serum after exposure, respectively. Changes in IL-1ra correlated with changes in FEV 1, bronchial responsiveness, oral temperature ( P<0·01) and blood white cell count ( P<0·05). IL-1β correlated significantly with temperature ( P<0·05). These results indicate that IL-1β and IL-1ra increase in peripheral blood following inhalation of swine house dust and may participate in and modulate the inflammatory response together with IL-6 and TNF-α.