Interleukin-1 Type Research Articles

Interleukin-1 type 1 receptor blockade attenuates the exaggerated exercise pressor reflex in male UC Davis type 2 diabetic mellitus rats.

An exaggerated exercise pressor reflex and peripheral neuropathy are both evoked by the same type of thinly myelinated afferents and are present in patients with type 2 diabetes mellitus (T2DM). Although it is known that the pro-inflammatory cytokine interleukin-1β (IL-1β) contributes to peripheral neuropathy, the effects of IL-1β on the exercise pressor reflex in T2DM are not known. Therefore, we aimed to determine the effect of IL-1 receptors on the exercise pressor reflex in T2DM. We compared changes in peak pressor (mean arterial pressure; ΔMAP), blood pressure index (ΔBPi), heart rate (ΔHR) and heart rate index (ΔHRi) responses to static and intermittent contractions and tendon stretch before and after peripheral IL-1 type 1 receptor blockade (anakinra, Kineret®) in T2DM and healthy male rats and IL-1 receptor activation (IL-1β) in healthy rats. Blocking IL-1 receptors significantly attenuated the ΔMAP and ΔBPi to static contraction in T2DM rats. Furthermore, blocking IL-1 receptors significantly attenuated the ΔMAP, ΔBPi and ΔHRi to intermittent contraction, and ΔMAP to tendon stretch in T2DM rats (all P<0.05). In addition, IL-1 receptor activation significantly exaggerated the ΔMAP and ΔBPi to static contraction and ΔMAP, ΔBPi and ΔHR to intermittent contraction in healthy rats, all P < 0.05. Furthermore, circulating IL-1β serum concentrations were significantly greater in T2DM rats than in healthy rats (P < 0.05). We conclude that IL-1 signalling contributes to the exaggerated exercise pressor reflex in T2DM, suggesting for the first time that inflammatory cytokines play a critical role in exaggerated blood pressure responses to exercise in those with T2DM. KEY POINTS: Chronic inflammation, a complication of type 2 diabetes mellitus (T2DM), causes increased production of pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumour necrosis factor-α. IL-1β has been shown to sensitize muscle afferents that conduct the exercise pressor reflex. We found blocking of IL-1 receptors by anakinra (Kineret®), an IL-1 type 1 receptor antagonist, significantly attenuated the exaggerated exercise pressor reflex in T2DM rats, but not in healthy rats. In addition, activating IL-1 receptors with IL-1β significantly augmented the exercise pressor reflex in healthy rats. Our findings suggest that IL-1 receptors, by mediating IL-1β signalling, play a role in exaggerating the exercise pressor reflex in T2DM. These results highlight the complex interplay between inflammation and the autonomic nervous system in regulating cardiovascular function, and the potential for using an FDA-approved IL-1 receptor antagonist, Kineret®, as a therapeutic approach to reduce adverse cardiovascular events during physical activity in those with T2DM.

Association between Interleukin-6 Gene Polymorphism (rs1800795 and rs1800796) and Type 2 Diabetes Mellitus in a Ghanaian Population: A Case-Control Study in the Ho Municipality.

There is no conclusive evidence on the association between interleukin- (IL-) 6 gene polymorphism and type 2 diabetes mellitus (type 2 DM). Thus, this study is aimed at evaluating the role of rs1800795 and rs1800796 polymorphisms in the pathogenesis of type 2 DM among Ghanaians in the Ho Municipality. We recruited into this hospital-based case-control study 174 patients with type 2 DM (75 DM alone and 99 with DM+HTN) and 149 healthy individuals between 2018 and 2020. Demographic, lifestyle, clinical, anthropometric, and haemodynamic variables were obtained. Fasting blood samples were collected for haematological, biochemical, and molecular analyses. Genomic DNA was extracted, amplified using Tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR) technique, and genotyped for IL-6 gene polymorphism. Logistic regression analyses were performed to assess the association between IL-6 gene polymorphism and type 2 DM. The minor allele frequency (MAF) of the rs1800795 and rs1800796 polymorphisms was higher in DM alone (57.5%, 62.0%) and DM with HTN groups (58.3%, 65.3%) than controls (33.1%, 20.0%). Carriers of the rs1800795GC genotype (aOR = 2.35, 95% CI: 1.13-4.90, p = 0.022) and mutant C allele (aOR = 2.41, 95% CI: 1.16-5.00, p = 0.019) as well as those who carried the rs1800796GC (aOR = 8.67, 95% CI: 4.00-18.90, p < 0.001) and mutant C allele (aOR = 8.84, 95% CI: 4.06-19.26, p = 0.001) had increased odds of type 2 DM. For both polymorphisms, carriers of the GC genotype had comparable levels of insulin, HOMA-IR, and fasting blood glucose (FBG) with those who carried the GG genotype. IL-6 levels were higher among carriers of the rs1800796GC variant compared to carriers of the rs1800796GG variant (p = 0.023). The rs1800796 polymorphism, dietary sugar intake, and exercise status, respectively, explained approximately 3% (p = 0.046), 3.2% (p = 0.038, coefficient = 1.456), and 6.2% (p = 0.004, coefficient = -2.754) of the variability in IL-6 levels, suggesting weak effect sizes. The GC genotype and mutant C allele are risk genetic variants associated with type 2 DM in the Ghanaian population. The rs1800796 GC variant, dietary sugar intake, and exercise status appear to contribute significantly to the variations in circulating IL-6 levels but with weak effect sizes.

Lipopolysaccharide (LPS) increases susceptibility to epilepsy via interleukin-1 type 1 receptor signaling

Epilepsy is the most common disease of the nervous system, characterized by aberrant normal brain activity. Neuroinflammation is a prominent feature in the brain in epileptic humans and animal models of epilepsy. However, it remains elusive as to how peripheral inflammation affects epilepsy. Herein we demonstrated significantly greater seizure susceptibility and severity of epilepsy under kainic acid (KA) via intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) in mouse model of epilepsy. Nissl staining was employed for assessment of the neuronal damage, immunofluorescence for staining of the microglial cells and astrocytes in the mouse brain slices, and ELISA for detection of the changes of inflammatory factors. We observed a smaller population of viable neurons in CA1 and CA3 regions, a greater population of IBA-1-positive and GFAP-positive cells, with a significant upregulation of IL-1β and IL-6 in hippocampus of epileptic mice when treated with LPS, indicating that LPS aggravates hippocampal neuron injury in epilepsy, and induces neuroinflammation in the hippocampus. In addition, we provide an evident increase in BrdU+/DCX+ and Nestin+ cell populations in dentate gyrus (DG) in LPS-treated group, versus saline group on epileptic mouse model, which demonstrated LPS treatment enhanced hippocampal neurogenesis. In order to investigate whether interleukin-1 type 1 (IL-1R1) signaling is involved in this process, we adopted IL-1R1 globally restored mice (IL-1R1GR/GR) as an IL-1R1 reporter to visualize labeling of IL-1R1 mRNA and protein by means of RFP staining. Strikingly, the RFP immunofluorescence revealed increased IL-1R1 expression in LPS-treated group, versus saline group. Further, blockage of central IL-1R1 alleviated seizure susceptibility and severity of epilepsy. In summary, our findings suggested that LPS could enhance central inflammatory response and aggravate the susceptibility to epileptic seizure, which we postulated to be mediated by IL-1R1.

Inhaled B7 alleviates bleomycin-induced pulmonary fibrosis in mice

Treatment options for the progression of pulmonary fibrosis (PF), which ultimately causes respiratory failure, are limited. According to recent studies, recombinant human relaxin is potentially therapeutic against fibrosis and contraction during pulmonary damage. However, the production of recombinant H2 relaxin is laborious and expensive, limiting its extensive application. Thankfully, alternative research has revealed that treatment with a single-chain peptide of relaxin attenuates organ fibrosis in rodent models too, with the production of a single-chain peptide of relaxin simple and cheap; it could be therapeutic against idiopathic pulmonary fibrosis. Here, we explored the probable inhibiting effects of B7, a B chain of recombinant human relaxin, on bleomycin-induced pulmonary inflammation. Inhaled B7 efficiently reduced the number of inflammatory leukocytes and neutrophils in the bronchoalveolar lavage fluid of mice with bleomycin-induced PF, significantly improved the structure of the damaged alveolar, reduced collagen deposition, suppressed the main pathological features of idiopathic pulmonary fibrosis, i.e. the expression of both pulmonary α-smooth muscle actin and pulmonary vimentin, and inhibited the transcription of inflammation and collagen deposition-related mRNAs, including fibronectin, α-smooth muscle actin (α-SMA), interleukin-1β (IL-1β), interleukin-6 (IL-6), and alpha-1 type 1 collagen (Col-1a), and the expression of inflammation-related proteins, such as IL-1β, IL-6, chemokines (KC), TIMP metallopeptidase inhibitor 1 (TIMP-1), and hydroxyproline (Hyp). Overall, our findings suggest that inhaled B7 exerts beneficial effects against pulmonary fibrosis via attenuating inflammation. It could be developed into a simple, highly effective therapeutic approach for pulmonary fibrosis.

Interleukin 1 beta-induced calcium signaling via TRPA1 channels promotes mitogen-activated protein kinase-dependent mesangial cell proliferation.

Glomerular mesangial cell (GMC)-derived pleiotropic cytokine, interleukin-1 (IL-1), contributes to hypercellularity in human and experimental proliferative glomerulonephritis. IL-1 promotes mesangial proliferation and may stimulate extracellular matrix accumulation, mechanisms of which are unclear. The present study shows that the beta isoform of IL-1 (IL-1β) is a potent inducer of IL-1 type I receptor-dependent Ca2+ entry in mouse GMCs. We also demonstrate that the transient receptor potential ankyrin 1 (TRPA1) is an intracellular store-independent diacylglycerol-sensitive Ca2+ channel in the cells. IL-1β-induced Ca2+ and Ba2+ influxes in the cells were negated by pharmacological inhibition and siRNA-mediated knockdown of TRPA1 channels. IL-1β did not stimulate fibronectin production in cultured mouse GMCs and glomerular explants but promoted Ca2+ -dependent cell proliferation. IL-1β also stimulated TRPA1-dependent ERK mitogen-activated protein kinase (MAPK) phosphorylation in the cells. Concomitantly, IL-1β-induced GMC proliferation was attenuated by TRPA1 and RAF1/ MEK/ERK inhibitors. These findings suggest that IL-1β-induced Ca2+ entry via TRPA1 channels engenders MAPK-dependent mesangial cell proliferation. Hence, TRPA1-mediated Ca2+ signaling could be of pathological significance in proliferative glomerulonephritis.

Inhibition of MLKL-dependent necroptosis via downregulating interleukin-1R1 contributes to neuroprotection of hypoxic preconditioning in transient global cerebral ischemic rats

BackgroundOur previous study indicated that hypoxic preconditioning reduced receptor interacting protein (RIP) 3-mediated necroptotic neuronal death in hippocampal CA1 of adult rats after transient global cerebral ischemia (tGCI). Although mixed lineage kinase domain-like (MLKL) has emerged as a crucial molecule for necroptosis induction downstream of RIP3, how MLKL executes necroptosis is not yet well understood. In this study, we aim to elucidate the molecular mechanism underlying hypoxic preconditioning that inactivates MLKL-dependent neuronal necroptosis after tGCI.MethodsTransient global cerebral ischemia was induced by the four-vessel occlusion method. Twenty-four hours before ischemia, rats were exposed to systemic hypoxia with 8% O2 for 30 min. Western blotting was used to detect the expression of MLKL and interleukin-1 type 1 receptor (IL-1R1) in CA1. Immunoprecipitation was used to assess the interactions among IL-1R1, RIP3, and phosphorylated MLKL (p-MLKL). The concentration of intracellular free calcium ion (Ca2+) was measured using Fluo-4 AM. Silencing and overexpression studies were used to study the role of p-MLKL in tGCI-induced neuronal death.ResultsHypoxic preconditioning decreased the phosphorylation of MLKL both in neurons and microglia of CA1 after tGCI. The knockdown of MLKL with siRNA decreased the expression of p-MLKL and exerted neuroprotective effects after tGCI, whereas treatment with lentiviral delivery of MLKL showed opposite results. Mechanistically, hypoxic preconditioning or MLKL siRNA attenuated the RIP3-p-MLKL interaction, reduced the plasma membrane translocation of p-MLKL, and blocked Ca2+ influx after tGCI. Furthermore, hypoxic preconditioning downregulated the expression of IL-1R1 in CA1 after tGCI. Additionally, neutralizing IL-1R1 with its antagonist disrupted the interaction between IL-1R1 and the necrosome, attenuated the expression and the plasma membrane translocation of p-MLKL, thus alleviating neuronal death after tGCI.ConclusionsThese data support that the inhibition of MLKL-dependent neuronal necroptosis through downregulating IL-1R1 contributes to neuroprotection of hypoxic preconditioning against tGCI.

Increased Soluble Interleukin-1 Type II Receptor Concentrations in Postoperative Patients and in Patients With Sepsis Syndrome

Plasma interleukin-1 (IL-1) activity is modulated in part through the simultaneous appearance of several inhibitors of IL-1 action, including interleukin-1 receptor antagonist (IL-1ra) and the soluble IL-1 type II receptor (IL-1RII). However, little is known concerning the plasma appearance of these inhibitors in patients following operative trauma or those with sepsis syndrome. In the present report, plasma IL-1beta, IL-1ra, and soluble IL-1RI and IL-1RII concentrations were evaluated in 118 patients with sepsis syndrome or after elective operative trauma. Plasma concentrations of IL-1ra increased significantly following elective operative repair of thoraco-abdominal and abdominal aortic aneurysms, and after bowel resection for inflammatory bowel disease, but did not increase after laparoscopic cholecystectomy. Plasma IL-1ra levels were also elevated in patients with sepsis syndrome. In contrast, soluble IL-1RII levels were only increased in patients after operative repair of thoraco-abdominal aortic aneurysms and in sepsis syndrome, whereas concentrations were unaffected by the other more modest surgical procedures. Plasma IL-1RI concentrations decreased in all postoperative patients in the first 24 hours after surgery. We conclude that both plasma IL-1ra and soluble IL-1RII concentrations often increase in sepsis and following some operative trauma. Less severe operative trauma increases the plasma concentration of only IL-1ra, whereas both IL-1ra and soluble IL-1RII are increased in patients with sepsis syndrome or following thoraco-abdominal aneurysm repair.

Mixture of enzyme-processed Panax ginseng and Gastrodia elata extract prevents UVB-induced decrease of procollagen type 1 and increase of MMP-1 and IL-6 in human dermal fibroblasts.

According to the previously described anti-photoaging effect of the enzyme-processed Panax ginseng extract and Gastrodia elata extract, we hypothesized that the combination of the two extracts would have superior effect to protect human skin from UVB radiation. Besides, the mixture of active components isolated from herbal extracts, ginsenoside F2, and α-gastrodin was investigated on the photo-protective capability. The expression of aging-related markers including matrix metalloproteinase-1 (MMP-1), interleukin-6 (IL-6), and procollagen type 1 was evaluated using ELISA kits. It was reported that the herbal extract at a Panax ginseng extract to Gastrodia elata extract ratio of 1:10 (w/w) and the compound mixture with equal proportion of ginsenoside F2 and α-gastrodin exhibited significant inhibition of MMP-1 and IL-6 production, and marked upregulation of procollagen type 1 formation. Thus, the combination of either the enzyme-processed herbal extracts or their active components would enhance the properties of prevention and treatment of UVB-induced skin damage.

Associations between psychosocial burden and prognostic biomarkers in patients with stable coronary heart disease – a STABILITY substudy

Abstract Background Psychosocial burden is associated with increased risk of cardiovascular (CV) events in patients with stable coronary heart disease (CHD). The underlying mechanisms linking psychosocial burden and CHD are unclear and might be explained by studying biomarkers known to be associated with CV risk. Methods 15,608 patients in the STABILITY trial completed a questionnaire on to what extent they were feeling down, had loss of interest, experienced financial stress and if they were living alone. Levels of high-sensitivity (hs) C-reactive protein (hs-CRP), interleukin-6 (IL-6), hs-troponin T (hs-TnT) and N-terminal pro-B type natriuretic peptide (NT-proBNP) were assessed at baseline. Associations between levels of psychosocial burden (sometimes, often/always vs. never/rarely) and biomarkers were evaluated in a linear model where geometric mean ratio of the log-transformed biomarker were calculated. Results Adjusted associations (age, gender and established CV risk factors) are presented in the table. Conclusion Psychosocial burden in patients with stable CHD was independently associated with elevated biomarkers. The underlying association is likely to be complex and involve multiple pathways. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): The STABILITY study was funded by GlaxoSmithKline. Roche Diagnostics, Rotkreuz, Switzerland, supported the research by providing the GDF-15 assay free of charge.

Ciliary neurotrophic factor (CNTF) and its receptor (CNTFRα) signal through MAPK/ERK pathway in human prostate tissues: a morphological and biomolecular study.

Ciliary neurotrophic factor (CNTF) is a member of interleukin-6 type cytokine family. The CNTF receptor complex is a heterodimer including gp130 and CNTF receptor α (CNTFRɑ) proteins triggering the activation of multiple intracellular signaling pathways including AKT/PI3K, MAPK/ERK and Jak/STAT pathways. At present no data are available on the localization of CNTF and CNTFRɑ in prostate as well as on the role of CNTF in this organ. In this study we have analyzed the localization of CNTF and CNTFRɑ by immunohistochemistry and we have used PWR-1E cell line as a model for normal glandular cell to investigate the role of this cytokine. Our results show that CNTF and CNTFRɑ are expressed in the staminal compart of the prostate and that CNTF selectively inhibits ERK pathway. In conclusion, we suggest that CNTF could be considered as key molecule to maintain the epithelium homeostasis via pERK downregulation by an autocrine mechanism. Further CNTF studies in prostate cancer could be useful to verify the potential role of this cytokine in carcinogenesis.

Ischemia and Reperfusion Injury in Donation after Circulatory Death Heart: Role of Interleukin-1

Donation after circulatory death donors (DCD) can increase the number of donors for heart transplantation, which currently depends on brain death donors (DBD) only. The DCD process induces substantial ischemia and reperfusion (I/R) injury mediated through cytokines. Interleukin-1 (IL-1) is one of the key downstream effectors of I/R injury. We hypothesize that genetic deletion of IL-1 type I receptor (lL-1RI-/-) or pharmacological inhibition of IL-1 with recombinant IL-1 receptor antagonist (IL-1Ra) may limit I/R injury in DCD hearts. Four groups of mice were studied, DBD wild type (DBD-WT), DCD-WT, DCD-IL-1RI-/-, and DCD-IL-Ra (n = 8 each). In anesthetized mice, clinical DCD process was simulated with preset warm ischemia time of 40minutes. In DBD group, hearts were procured without ischemia and served as controls. All hearts were reanimated for 90 minutes on a Langendorff system with oxygenated Krebs-Henseleit buffer at steady 76mmHg pressure at 37°C. Heart rate, developed pressure (DP), +dP/dt and -dP/dt were measure as functional parameters. Cardiac troponin I (cTnI) was measured in the eluate as marker of cardiac injury. Heart rate was higher in all the DCD groups (see table). DP, + and -dP/dt were significantly reduced in DCD-WT compared to DBD group (all p<0.05). Genetic deletion of IL-1RI was protective from DCD I/R injury with low cTnI release and preserved heart function (all p<0.05). Pharmacologic blockage of IL-1 afforded protection from I/R injury in DCD hearts, but the physiologic parameters did not attain statistical significance. IL-1 contributes to the I/R injury associated with the DCD process. Pharmacologic blockade of IL-1 has a potential to limit I/R injury and preserve function in DCD hearts.

Myeloid Cells Enriched for a Dendritic Cell Population From People Living With HIV Have Altered Gene Expression Not Restored by Antiretroviral Therapy.

Antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infections has been designed to optimize CD4 T-cell survival and limit HIV replication. Cell types other than CD4 T cells such as monocytes/macrophage, dendritic cells, and granulocytes (collectively known as myeloid cells), are generally not considered in the development of ART protocols. Myeloid dendritic cells (mDCs) are the most potent inducers of CD4 T-cell activation and central to the regulation of immune responses. mDCs in the blood are decreased in number, altered in function, and implicated in promoting HIV latency in people living with HIV (PLWH). We found that cells enriched for mDC in PLWH had transcriptional changes compared to mDC from HIV uninfected individuals, some of which were not completely restored by ART. In contrast, other mDC functions such as interleukin-1 signaling and type I interferon pathways were restored by ART. Some of the transcriptional changes in mDC not completely reversed by ART were enriched in genes that are classically associated with cells of the monocyte/macrophage lineage, but new single-cell RNA sequencing studies show that they are also expressed by a subset of mDC. A cellular enzyme, acyloxyacyl hydrolase (AOAH), important for lipopolysaccharide (LPS) detoxification, had increased transcription in mDC of PLWH, not restored by ART. It is possible that one reason ART is not completely successful in PLWH is the failure to phenotypically change the mDCs. Thus, inability of ART to be completely effective might involve myeloid cells and the failure to restore mDC function as measured by gene transcription. We suggest that mDC and myeloid cells should be considered in future combination ART development.

Modulation of Neural Networks byInterleukin-1.

Interleukin-1 (IL-1) is an inflammatory cytokine that has been shown to modulate neuronal signaling in homeostasis and diseases. In homeostasis, IL-1 regulates sleep and memory formation, whereas in diseases, IL-1 impairs memory and alters affect. Interestingly, IL-1 can cause long-lasting changes in behavior, suggesting IL-1 can alter neuroplasticity. The neuroplastic effects of IL-1 are mediated via its cognate receptor, Interleukin-1 Type 1 Receptor (IL-1R1), and are dependent on the distribution and cell type(s) of IL-1R1 expression. Recent reports found that IL-1R1 expression is restricted to discrete subpopulations of neurons, astrocytes, and endothelial cells and suggest IL-1 can influence neural circuits directly through neuronal IL-1R1 or indirectly via non-neuronal IL-1R1. In this review, we analyzed multiple mechanisms by which IL-1/IL-1R1 signaling might impact neuroplasticity based upon the most up-to-date literature and provided potential explanations to clarify discrepant and confusing findings reported in the past.

Anakinra Therapy for Non-cancer Inflammatory Diseases.

Interleukin-1 (IL-1) is the prototypical inflammatory cytokine: two distinct ligands (IL-1α and IL-1β) bind the IL-1 type 1 receptor (IL-1R1) and induce a myriad of secondary inflammatory mediators, including prostaglandins, cytokines, and chemokines. IL-1α is constitutively present in endothelial and epithelial cells, whereas IL-1β is inducible in myeloid cells and released following cleavage by caspase-1. Over the past 30 years, IL-1-mediated inflammation has been established in a broad spectrum of diseases, ranging from rare autoinflammatory diseases to common conditions such as gout and rheumatoid arthritis (RA), type 2 diabetes, atherosclerosis, and acute myocardial infarction. Blocking IL-1 entered the clinical arena with anakinra, the recombinant form of the naturally occurring IL-1 receptor antagonist (IL-1Ra); IL-1Ra prevents the binding of IL-1α as well as IL-1β to IL-1R1. Quenching IL-1-mediated inflammation prevents the detrimental consequences of tissue damage and organ dysfunction. Although anakinra is presently approved for the treatment of RA and cryopyrin-associated periodic syndromes, off-label use of anakinra far exceeds its approved indications. Dosing of 100 mg of anakinra subcutaneously provides clinically evident benefits within days and for some diseases, anakinra has been used daily for over 12 years. Compared to other biologics, anakinra has an unparalleled record of safety: opportunistic infections, particularly Mycobacterium tuberculosis, are rare even in populations at risk for reactivation of latent infections. Because of this excellent safety profile and relative short duration of action, anakinra can also be used as a diagnostic tool for undefined diseases mediated by IL-1. Although anakinra is presently in clinical trials to treat cancer, this review focuses on anakinra treatment of acute as well as chronic inflammatory diseases.

Immunohistochemical Expression of IL1-R1 in the TMJ Disks

The fibrocartilaginous disk in the temporomandibular joint (TMJ) consists of collagen fibers and fibroblast-like cells. It plays an important role in pressure distribution of the TMJ. When a disk is chronically overloaded, it may undergo structural changes that have pathological consequences. Cytokines and their receptors have been shown to be present in the synovial fluid of patients with internal derangement and osteoarthritis. Interleukin-1 (IL-1) acts as a pro-inflammatory cytokine. Most of the IL-1 signal has been shown to be transmitted through Interleukin-1 type 1 receptor (IL-1R1) in T lymphocytes as well as B lymphocytes and monocytes. In patients with internal derangements, fibroblasts and other cells that are under chronic trauma may release IL-1 as a protective mechanism. It is hypothesized that in TMJ dysfunction, IL-1R1 expression levels may be elevated. The majority of studies have been performed with synovial fluid, animal models, or cadavers. Therefore, the objective of this study is to determine the association of IL-1R1 expression in the disks of patients with TMJ dysfunctions using an immunihistochemical approach to evaluate the joint disk.

Molecular cloning and expression analysis of interleukin-1β and interleukin-1 receptor type I genes in yellow catfish (Pelteobagrus fulvidraco): Responses to challenge of Edwardsiella ictaluri.

Interleukin-1β (IL-1β) is one of the pivotal early pro-inflammatory cytokines, which play important roles in regulating immune response and inducing a series of inflammatory reactions to infections. Interleukin-1 type I receptor (IL-1RI) is a receptor of the IL-1β that can mediate IL-1-dependent activation. In this study, partial cDNA sequences of the Pf_IL-1β and Pf_IL-1RI genes were cloned from yellow catfish (Pelteobagrus fulvidraco). The open reading frames (ORF) of Pf_IL-1β and Pf_IL-1RI genes encode putative peptides of 280 and 543 amino acids, respectively. The deduced amino acid sequences of these two genes shared highly conserved structures with those from other teleosts. Quantitative real-time PCR results showed that the Pf_IL-1β mRNA had relatively high expression levels in trunk kidney and blood, and the Pf_IL-1RI mRNA was highly expressed in blood and had relatively high expression level in liver. Ontogenetic expression analyses indicate that the Pf_IL-1β and Pf_IL-1RI genes may play important roles during the embryonic developmental stages. The mRNA expression levels of Pf_IL-1β and Pf_IL-1RI genes were up-regulated in the trunk kidney, head kidney, blood, spleen, heart and liver after Edwardsiella ictaluri challenge. Western blot analyses showed that Pf_IL-1β protein was highly expressed in the spleen and head kidney, but not in the fin of adult individuals. These results suggest that the Pf_IL-1β and Pf_IL-1RI genes may play significant roles in the immune regulation and defense against E. ictaluri in the yellow catfish.

Involvement of interleukin-1 type 1 receptors in lipopolysaccharide-induced sickness responses

Sickness responses to lipopolysaccharide (LPS) were examined in mice with deletion of the interleukin (IL)-1 type 1 receptor (IL-1R1). IL-1R1 knockout (KO) mice displayed intact anorexia and HPA-axis activation to intraperitoneally injected LPS (anorexia: 10 or 120µg/kg; HPA-axis: 120µg/kg), but showed attenuated but not extinguished fever (120µg/kg). Brain PGE2 synthesis was attenuated, but Cox-2 induction remained intact. Neither the tumor necrosis factor-α (TNFα) inhibitor etanercept nor the IL-6 receptor antibody tocilizumab abolished the LPS induced fever in IL-1R1 KO mice. Deletion of IL-1R1 specifically in brain endothelial cells attenuated the LPS induced fever, but only during the late, 3rd phase of fever, whereas deletion of IL-1R1 on neural cells or on peripheral nerves had little or no effect on the febrile response. We conclude that while IL-1 signaling is not critical for LPS induced anorexia or stress hormone release, IL-1R1, expressed on brain endothelial cells, contributes to the febrile response to LPS. However, also in the absence of IL-1R1, LPS evokes a febrile response, although this is attenuated. This remaining fever seems not to be mediated by IL-6 receptors or TNFα, but by some yet unidentified pyrogenic factor.

Pirfenidone attenuates bleomycin-induced pulmonary fibrosis in mice by regulating Nrf2/Bach1 equilibrium

BackgroundOxidative stress is one of the important factors involved in the pathogenesis of idiopathic pulmonary fibrosis (IPF). The equilibrium of Nuclear factor-erythroid-related factor 2 (Nrf2)/[BTB (broad-complex, tramtrack and bric-a-brac) and CNC (cap‘n’collar protein) homology 1, Bach1] determines the expression level of antioxidant factors, further regulating the function of oxidation/antioxidation capacity. Pirfenidone (PFD) is one of two currently for IPF therapy approved drugs. PFD regulates intracellular antioxidants, inhibits secretion of inflammatory cytokines and collagen synthesis. However the mechanisms of its antioxidant effects remain elusive.MethodsEffects of PFD treatment were studied in mouse lung fibroblasts (MLF) following induction by transforming-growth factor beta 1 (TGF-β1) and in mice following bleomycin-induced lung fibrosis. The mRNA and protein levels of oxidative stress-related factors Nrf2/Bach1 and their downstream antioxidant factors heme oxygenase-1 (Ho-1) and glutathione peroxidase 1 (Gpx1) were determined by RT-PCR and Western blot. Fibrosis-related cytokines interleukin-6 (IL-6) and myofibroblast markers type 1 collagen α1 (COL1A1) levels in supernate of MLF, serum, and bronchoalveolar lavage fluid (BALF) as well as malondialdehyde (MDA) in serum and BALF were detected by ELISA, reactive oxygen species (ROS) generation was measured by 2′,7′- dichlorofluorescin diacetate (DCFH-DA) assay and lung pathological/morphological alterations in mice were observed by HE and Masson to assess the antioxidant mechanism and therapeutic effects on pulmonary fibrosis induced by bleomycin.ResultsPFD inhibited Bach1 mRNA and protein expressions in mouse lung fibroblasts induced by TGF-β1 and lung tissues with pulmonary fibrosis induced by bleomycin. Furthermore, it improved Nrf2, Ho-1 and Gpx1 mRNA and protein expressions. After PFD treatment, COL1A1and IL-6 levels in supernate of MLF, serum, and BALF as well as ROS in lung tissues and MDA in serum and BALF from a mouse with pulmonary fibrosis were significantly decreased, and the infiltration of lung inflammatory cells and fibrosis degree were alleviated.ConclusionsTheraputic effects of PFD for IPF were involved in Nrf2/Bach1 equilibrium which regulated the capacity of oxidative stress. The study provided new insights into the antioxidant mechanism of PFD.

Correlation between serum interleukin-6 level and type 1 diabetes mellitus: A systematic review and meta-analysis

ObjectiveThis report aimed to explore the association between the change of circulating interleukin-6 (IL-6) in patients and the development of type 1 diabetes mellitus (T1DM). MethodsFour databases (PubMed, CNKI, WanFang and Civip) were used to search and list all clinical case-control studies about serum IL-6 level in T1DM patients between Jan 1, 2000 and Aug 31, 2016. ResultsA total of 20 case-control studies with 1238 T1DM patients and 742 healthy controls were included in this study. Compared to healthy controls, the serum content of IL-6 in patients with T1DM was significantly greater (overall: SMD, 1.49; 95% CI, 1.04 to 1.93; p<0.001), and notably increased in all subgroup with different age, ethnic and disease duration (all p<0.001). Furthermore, the analysis in subgroup exhibited that serum levels of IL-6 in the age greater than 20-year old (SMD, 1.64; 95% CI, 0.57–2.71; p<0.001), the diseased duration among 0–10years (SMD, 2.43; 95% CI, 1.42–3.44; p<0.001) and the sorted American group (SMD, 1.68; 95% CI, 0.85–2.51; p<0.001) were higher than those in control groups. ConclusionsPatients with T1DM were found to be linked to elevated level of serum IL-6, which the age, ethnic and disease durations in T1DM patients had no effect on the serum IL-6 levels for promoting diabetes mellitus.

Due to interleukin-6 type cytokine redundancy only glycoprotein 130 receptor blockade efficiently inhibits myeloma growth.

Interleukin-6 has an important role in the pathophysiology of multiple myeloma where it supports the growth and survival of the malignant plasma cells in the bone marrow. It belongs to a family of cytokines which use the glycoprotein 130 chain for signal transduction, such as oncostatin M or leukemia inhibitory factor. Targeting interleukin-6 in plasma cell diseases is currently evaluated in clinical trials with monoclonal antibodies. Here, efforts were made to elucidate the contribution of interleukin-6 and glycoprotein 130 signaling in malignant plasma cell growth in vivo In the xenograft severe combined immune deficiency model employing our interleukin-6-dependent plasma cell line INA-6, the lack of human interleukin-6 induced autocrine interleukin-6 production and a proliferative response to other cytokines of the glycoprotein 130 family. Herein, mice were treated with monoclonal antibodies against human interleukin-6 (elsilimomab/B-E8), the interleukin-6 receptor (B-R6), and with an antibody blocking glycoprotein 130 (B-R3). While treatment of mice with interleukin-6 and interleukin-6 receptor antibodies resulted in a modest delay in tumor growth, the development of plasmacytomas was completely prevented with the anti-glycoprotein 130 antibody. Importantly, complete inhibition was also achieved using F(ab')2-fragments of monoclonal antibody B-R3. Tumors harbor activated signal transducer and activator of transcription 3, and in vitro, the antibody inhibited leukemia inhibitory factor stimulated signal transducer and activator of transcription 3 phosphorylation and cell growth, while being less effective against interleukin-6. In conclusion, the growth of INA-6 plasmacytomas in vivo under interleukin-6 withdrawal remains strictly dependent on glycoprotein 130, and other glycoprotein 130 cytokines may substitute for interleukin-6. Antibodies against glycoprotein 130 are able to overcome this redundancy and should be explored for a possible therapeutic window.