Overproduction Of Interleukin-6 Research Articles

Structural basis of signaling complex inhibition by IL-6 domain-swapped dimers.

Interleukin-6 (IL-6) is a multifaceted cytokine essential in many immune system processes and their regulation. It also plays a key role in hematopoiesis, and in triggering the acute phase reaction. IL-6 overproduction is critical in chronic inflammation associated with autoimmune diseases like rheumatoid arthritis and contributes to cytokine storms in COVID-19 patients. Over 20 years ago, researchers proposed that IL-6, which is typically monomeric, can also form dimers via a domain-swap mechanism, with indirect evidence supporting their existence. The physiological significance of IL-6 dimers was shown in B-cell chronic lymphocytic leukemia. However, no structures have been reported so far. Here, we present the crystal structure of an IL-6 domain-swapped dimer that computational approaches could not predict. The structure explains why the IL-6 dimer is antagonistic to the IL-6 monomer in signaling complex formation and provides insights for IL-6 targeted therapies.

TAX1BP1/A20 inhibited TLR2-NF-κB activation to induce tolerant expression of IL-6 in endothelial cells

The inflammatory cascadedriven by interleukin-6 (IL-6) plays a crucial role in the initiation and progression of chronic inflammatory conditions such as atherosclerosis. Research has demonstrated that prolonged exposure to inflammatory stimuli leads to the development of “immune tolerance” in specialized immune cells such as monocytes and macrophages, serving as a mechanism to prevent tissue damage and curb the inflammatory cascade. However, our recent investigation revealed that immune tolerance did not effectively regulate the production of IL-6 in human umbilical vein endothelial cells (HUVECs) when stimulated by a Toll-like receptor 2 (TLR2) ligand Pam3CSK4, which is a potent activator of the pro-inflammatory transcription factor NF-κB. Furthermore, the negative regulator of NF-κB signaling, A20, was ineffective in suppressing TLR2-induced IL-6 synthesis in this context. Notably, all A20 auxiliary molecules, with the exception of TAX1BP1, were found to be significantly expressed in HUVECs. DNA methylation in TAX1BP1 was confirmed in GEO database. According to the information provided, it is hypothesized that altered DNA methylation in HUVECs could potentially lead to decreased expression of TAX1BP1, thereby impeding A20′s capacity to modulate continuous activation of the TLR2-NF-κB pathway. This may consequently lead to unregulated production of IL-6, evading immune tolerance mechanisms. Subsequent investigations suggested that demethylating TAX1BP1 could enhance its expression, potentially reducing the endogenous IL-6 levels induced by repeated TLR2 stimulation and restoring A20′s inhibitory role in NF-κB signaling. Additionally, over-expression of TAX1BP1 coulddecrease the production of atherosclerosis-associated cytokines like IL-6, MCP-1, ICAM-1, and VCAM-1, while increasing NO release following repeated Pam3cks4 stimulation, along with enhanced co-localization of TAX1BP1 and A20. These findings indicate that inducing immune tolerance in endothelial cells may effectively suppress endogenous IL-6 production and halt the IL-6-mediated inflammatory cascade, with TAX1BP1/A20 identified as crucial components in this process.These insights provide novel perspectives and potential targets for therapeutic strategies in inflammatoryimmunological disorders involving the overproduction of IL-6.

Chronic Expression of Interleukin-10 Transgene Modulates Cardiac Sympathetic Ganglion Resulting in Reduced Ventricular Arrhythmia.

The cardiac autonomic nervous system (CANS) is intimately connected to the regulation of electrophysiology and arrhythmogenesis in cardiac systems. This work aimed at investigating whether interleukin-10 (IL-10) could effectively modulate CANS and suppress ischemia-induced ventricular arrhythmia (VA) through chronically acting on the cardiac sympathetic ganglion (CSG). Using an adeno-associated virus (AAV), we achieved local chronic overproduction of IL-10 in the CSG, left stellate ganglion (LSG). As a result, in the IL-10 group, we observed a decreased number of tyrosine hydroxylase-positive (TH+) cells in the LSG. IL-10 markedly downregulated the nerve growth factor, synaptophysin, as well as growth-associated protein 43 expression. In vivo, results from ambulatory electrocardiography showed that IL-10 overexpression significantly inhibited the cardiac sympathetic nervous system activity and improved heart rate variability. Meanwhile, we observed decreased LSG function as well as prolonged ventricular effective refractory period and suppressed VA after myocardial infarction (MI) in the IL-10 group. In addition, IL-10 overexpression attenuated inflammation and decreased norepinephrine levels in the myocardium after acute MI. In conclusion, our data suggest that chronic IL-10 overexpression modulates cardiac sympathetic nerve remodeling and suppresses VA induced by MI. Neuromodulation through AAV-mediated IL-10 overexpression may have the characteristics of and advantages as a potential neuroimmunotherapy for preventing MI-induced VAs.

Single nucleotide polymorphisms in the Dicer gene modify the risk of systemic lupus erythematosus

Objective MicroRNA-related single-nucleotide polymorphisms (miR-SNPs) can alter microRNA (miRNA) expression profiles, thereby influencing the risk of rheumatic diseases. Herrin a case control study, six miR-SNPs in miRNA processing machinery genes, namely RAN (rs14035), XPO5 (rs11077), Dicer (rs3742330), GEMIN3 (rs197412), GEMIN4 (rs2740348), and TNRC6B (rs9623117), were genotyped to assess their correlation with the risk of systemic lupus erythematosus (SLE). Methods We included 119 patients with SLE and 130 healthy controls. The genotypes of the six miR-SNPs were determined using polymerase chain reaction (PCR). Serum cytokine levels were assessed using a cytometric bead array, and fluorescent probe technology was used to determine plasma reactive oxygen species (ROS) levels. Results The AA genotype of Dicer was correlated with a 0.566-fold decreased risk of SLE compared with that of the AG + GG genotype (odds ratio, 0.566; 95% CI, 0.342–0.935; p = .026), and the rs3742330 A allele was associated with a significantly decreased risk of SLE ( p = .035) compared with that of the rs3742330G allele. Additionally, AA genotype carriers exhibited lower levels of interleukin-6 (IL-6) in the blood ( p = .013). Subsequent analysis revealed increased ROS production in patients with SLE than that in the controls (621.042 ± 425.285 vs 499.966 ± 302.273, p = .011). Conclusion Our findings suggest that ROS generation participates in SLE pathogenesis. The identification of Dicer gene SNP rs3742330 as a potential modifier of SLE risk via mediating IL-6 overproduction suggests a potential avenue for targeted interventions to manage SLE and its associated immune dysregulation.

Tocilizumab; A Potential Remedy Against The Ever-Evolving Threat Of Coronavirus-2 (SARS-Cov-2).

Madam, Coronavirus-2 (SARS-CoV-2) is a novel positive single-strand RNA virus that is the causative agent of COVID-19, which originated in Wuhan, China, at the end of December 2019. Since the beginning of 2020, this virus has taken the world by storm, brought the globe to an absolute crawl for the last two years, and overburdened healthcare facilities in numerous countries. The Coronavirus-2 (SARS-CoV-2) virus is transmitted via aerosolized droplets, and once the virus finds itself inside the host's body, it undergoes an incubation period between 6-7 days. After the viral incubation period passes, the patient suffers from fever, cough, dyspnea, myalgia, and, in severe cases, hypoxia that requires hospitalization and mechanical ventilation.1 The pathogenesis of COVID-19 involves the dysregulation of the host immune response, which may lead to the development of acute respiratory distress syndrome in the host. The dysfunction of the host's immune response involves the hyperactivation of the humoral pathway, resulting in the overproduction of interleukin-6. Elevated levels of Interleukin-6 may lead to the development of numerous pathologies like respiratory failure, shock, and multiorgan dysfunction. This derangement of the host immune response would act as a potential target for several therapeutic agents to relieve COVID-19 symptoms.2 One such therapeutic agent is Toculimizab, which is a recombinant humanized anti-interleukin 6 receptor monoclonal antibody that functions by binding to membrane IL-6 R, thus preventing the formation of the complex with IL-6 and blocking the signal transmission. It is used in several inflammatory immune diseases such as Systemic Sclerosis, Giant Cell Arteritis, Takayasu Arteritis, etc. Tocilizumab has been shown to improve the hyperinflammatory and hypercoagulable state of COVID- 19 patients by reducing the circulating inflammatory biomarkers.3 To support the use and clinical efficacy of Tocilizumab in the hospitalized patient, a 2021 metaanalysis by Kyriakopoilous C. et al. showed the effects of Tocilizumab on mortality amongst Hospitalized COVID-19 patients and to see whether mechanical ventilation would be necessary once Tocilizumab was administered. This research was a combination of observational studies and randomized control trials. The results revealed a reduction in mortalities among 27,004 hospitalized COVID-19 patients. In the meta-analysis observational studies, there was an overall 31% decrease in mortality In the randomized control trials, there was an 11% decrease in mortality, along with a 19% decrease in the need for mechanical ventilation, showing that Tocilizumab was beneficial for all hospitalized patients.4 Continued...

The overproduction of interleukin-6 in pheochromocytoma and its impact on systemic inflammation compared to other types of adrenal tumors

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Pigment epithelium-derived factor is an interleukin-6 antagonist in the RPE: Insight of structure-function relationships.

Retinal and choroidal inflammatory lesions increase the levels of the pro-inflammatory cytokine interleukin-6 (IL-6). Pigment epithelium-derived factor (PEDF) has anti-inflammatory properties, but it is not known if it can prevent the production of IL-6 by the retinal pigment epithelium. To investigate the anti-inflammatory effects of PEDF in the RPE, we used human ARPE-19 cells stimulated with human recombinant tumor necrosis factor-alpha (TNF-α) to induce overexpression of the IL6 gene. We found that the viability of ARPE-19 cells decreased by 22% with TNF-α at 10ng/ml, being drastically decreased at ≥50ng/ml. TNF-α at 5-100ng/ml elevated the production and secretion of IL-6 protein, as measured by ELISA. To challenge the TNF-α-mediated stimulation of IL-6, we used recombinant human PEDF protein. PEDF at 100nM recovered the TNF-α-mediated loss of cell viability and repressed IL-6 gene expression as determined by RT-PCR. PEDF at 10-100nM attenuated the IL-6 protein secretion in a dose dependent fashion (IC50 = 65nM), being abolished with 100nM PEDF. To map the region that confers the IL-6 blocking effect to the PEDF polypeptide, we used chemically synthesized peptides designed from its biologically active domains, pro-death 34-mer, and pro-survival 44-mer and 17-mer (H105A), to challenge the IL-6 overproduction. The pro-survival peptides recovered the TNF-α-mediated cell viability loss, and inhibited IL-6 secretion, while the 34-mer did not have an effect, suggesting a role for the pro-survival domain in blocking TNF-α-mediated cell death and IL-6 stimulation. Our findings position PEDF as a novel antagonistic agent of IL-6 production in RPE cells, underscoring its use for the management of retinal disease-related inflammation.

Rilonacept and Other Interleukin-1 Inhibitors in the Treatment of Recurrent Pericarditis.

Pericarditis is the commonest form of pericardial disease. Unfortunately, despite optimal treatment, approximately 15-30% of patients with acute pericarditis have recurrence. Many of these patients are refractory to colchicine, and become corticosteroid-dependent. Recurrent pericarditis severely impairs quality of life, and is associated with significant morbidity. Inflammasome formation and overproduction of interleukin (IL)-1 have been found to drive the systemic inflammatory response in recurrent autoinflammatory pericarditis. Several IL-1 inhibitors have been evaluated for their usefulness as therapeutic options. Rilonacept is a dimeric fusion protein that functions as a soluble decoy receptor that binds to both IL-1α and IL-1β, thereby inhibiting the IL-1 pathway. It is safe and efficacious in the treatment of recurrent pericarditis in the RHAPSODY II and III trials. Anakinra is a recombinant IL-1 receptor antagonist that blocks the action of circulating IL-1α and IL-1β. It has also been shown to be safe and efficacious in the AIRTRIP and IRAP studies. Canakinumab is a selective human monoclonal antibody against IL-1β, and data on its use in recurrent pericarditis is scarce. Several questions regarding IL-1 inhibitor therapy, such as the duration of treatment and the recommended tapering protocols, as well as their use in special populations like pregnant or lactating women, remain unanswered and need to be addressed in future studies.

Anti-Cancer Properties of Clove Bud Essential Oil in Colon Cancer Cell Line

Colon cancer is a type of cancer that begins in the large intestine (colon). Its aggression is owing to late diagnosis so poor prognosis and higher mortality rate are reported. Colon cancer has become a thorny research region that requires more examination in cellular pathways involved in its emergency. Here we aim to investigate the possible anticancer properties of the clove oil as natural and popular oil in colon cancer CaCo-2 cells. Accordingly, cell viability rate and number of survived cells were monitored in response to the clove oil treatment compared with the black seed oil and DMSO-treatment. Lactate dehydrogenase (LDH) production was also considered as an indicator for necrotic event following treatment. The relative gene expression of Raf-1, MEK, and ERK was detected as proliferation effectors that linked to the expression profile of the tumor suppressor genes PTEN and TP53 using quantitative real-time PCR (qRT-PCR). Interestingly, here we identified Raf-1 pathway as a potential targeted singling by the clove oil resulted in controlling colon cancer cell proliferation. The current study elucidates the anticancer activities of the clove oil in colon cancer division through restoring the relative gene expression of PTEN and TP53 accompanied by over-production of interleukin 1 alpha (IL-1α) and IL-1β. Accordingly, treatment of the CaCo-2 cells with different concentrations of the clove oil increased programmed cells cell death (PCD) and inhibited the proliferation singling when compared with the black seed oil. Collectively, our results demonstrate that controlling of Raf-1 activity and PCD by clove oil treatment provide evidence for its anticancer effect in colon cancer cells.

The Clinical Chameleon of Autoinflammatory Diseases in Children.

The very first line of defense in humans is innate immunity, serving as a critical strongpoint in the regulation of inflammation. Abnormalities of the innate immunity machinery make up a motley group of rare diseases, named ‘autoinflammatory’, which are caused by mutations in genes involved in different immune pathways. Self-limited inflammatory bouts involving skin, serosal membranes, joints, gut and other districts of the human body burst and recur with variable periodicity in most autoinflammatory diseases (ADs), often leading to secondary amyloidosis as a long-term complication. Dysregulated inflammasome activity, overproduction of interleukin (IL)-1 or other IL-1-related cytokines and delayed shutdown of inflammation are pivotal keys in the majority of ADs. The recent progress of cellular biology has clarified many molecular mechanisms behind monogenic ADs, such as familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome (or ‘autosomal dominant familial periodic fever’), cryopyrin-associated periodic syndrome, mevalonate kinase deficiency, hereditary pyogenic diseases, idiopathic granulomatous diseases and defects of the ubiquitin-proteasome pathway. A long-lasting history of recurrent fevers should require the ruling out of chronic infections and malignancies before considering ADs in children. Little is known about the potential origin of polygenic ADs, in which sterile cytokine-mediated inflammation results from the activation of the innate immunity network, without familial recurrency, such as periodic fever/aphthous stomatitis/pharyngitis/cervical adenopathy (PFAPA) syndrome. The puzzle of febrile attacks recurring over time with chameleonic multi-inflammatory symptoms in children demands the inspection of the mixture of clinical data, inflammation parameters in the different disease phases, assessment of therapeutic efficacy of a handful of drugs such as corticosteroids, colchicine or IL-1 antagonists, and genotype analysis to exclude or confirm a monogenic origin.

Profiling Differential Effects of 5 Selective Serotonin Reuptake Inhibitors on TLRs-Dependent and -Independent IL-6 Production in Immune Cells Identifies Fluoxetine as Preferred Anti-Inflammatory Drug Candidate

Excessive proinflammatory cytokine production induced by abnormal activation of Toll-like receptor (TLR) signaling, for example, by SARS-CoV-2 infection, can cause a fatal cytokine storm. The selective serotonin reuptake inhibitors (SSRIs) fluoxetine and fluvoxamine, used to treat depression, were recently reported to reduce the risk of severe disease in patients with coronavirus disease 2019 (COVID-19), but the mechanisms of the anti-inflammatory effects of SSRIs, and which SSRI would be most suitable as an anti-inflammatory drug, remain unclear. Here, we examined the inhibitory effects of 5 FDA-approved SSRIs, paroxetine, fluoxetine, fluvoxamine, sertraline and escitalopram, on the production of interleukin-6 (IL-6) induced by stimulation with multiple TLR agonists in murine macrophages and dendritic cells, and on the production of cytokines induced by concanavalin A in murine lymphocytes. In J774.1 murine macrophage cells, pretreatment with SSRIs significantly suppressed IL-6 release induced by TLR3 agonist poly(I:C), TLR4 agonist LPS or TLR9 agonist CpG ODN, but did not affect IL-6 release induced by TLR7 agonists imiquimod or resiquimod. In accordance with the results obtained in J774.1 cells, pretreatment with SSRIs also suppressed IL-6 release induced by a TLR3, TLR4 or TLR9 agonist in bone marrow-derived dendritic cells and peritoneal cells of C57BL/6 mice. On the other hand, interestingly, sertraline alone among the SSRIs amplified IL-6 production induced by TLR7 agonists in murine dendritic cells, though not in macrophages. Concanavalin A-induced production of IL-6 or IL-2 in murine lymphocytes was suppressed by SSRIs, suggesting that SSRIs also inhibit TLRs-independent IL-6 production. Since SSRIs suppressed both IL-6 production induced by multiple TLR agonists in macrophages or dendritic cells and TLR-independent IL-6 production in lymphocytes, they are promising candidates for treatment of patients with cytokine storm, which is mediated by overactivation of multiple TLRs in a complex manner, leading to the so-called IL-6 amplifier, an IL-6 overproduction loop. However, the 5 SSRIs examined here all showed different effects. Overall, our results suggest that fluoxetine may be the most promising candidate as an anti-inflammatory drug. An examination of the structural requirements indicated that the N-methyl group of fluoxetine has a critical role in the inhibition of IL-6 production.

Short stature as an initial presenting presentation of unicentric Castleman disease in a child: A case report with long-term follow-up and a literature review.

Short stature is a common clinical condition in paediatric outpatient clinics and is associated with various clinical conditions, ranging from normal variants to severe diseases. Short stature is known to be caused by chronic inflammatory conditions, in which over-produced inflammatory cytokines are reported to be involved in growth suppression. Castleman disease is a rare lymphoproliferative disorder known as a chronic inflammatory disease with overproduction of interleukin 6, which often causes systemic symptoms such as fever, fatigue, weight loss, and night sweats. Here, we report the case of a 10-year-old female diagnosed with unicentric Castleman disease, who presented with short stature as the sole clinical sign but lacked typical systemic symptoms of Castleman disease. An elevated serum C-reactive protein level led us to suspect a chronic inflammatory condition, and we found an intra-abdominal tumour that was histopathologically confirmed as Castleman disease. The tumour removal resulted in a steady catch-up in her height in the six years following the surgery. We also present a brief review of relevant literature on paediatric cases of Castleman disease associated with growth impairment. Clinicians should be aware that chronic inflammatory conditions can cause growth impairment, which may be a key clinical manifestation of such conditions.

The Preferential Use of Anakinra in Various Settings of FMF: A Review Applied to an Updated Treatment-Related Perspective of the Disease.

Familial Mediterranean fever (FMF), the most frequent monogenic autoinflammatory disease, is manifested with recurrent and chronic inflammation and amyloid A (AA) amyloidosis, driven by overproduction of interleukin 1 (IL-1) through an activated pyrin inflammasome. Consequently, non-responsiveness to colchicine, the cornerstone of FMF treatment, is nowadays addressed by IL-1- blockers. Each of the two IL-1 blockers currently used in FMF, anakinra and canakinumab, has its own merits for FMF care. Here we focus on anakinra, a recombinant form of the naturally occurring IL-1 receptor antagonist, and explore the literature by using PubMed regarding the utility of anakinra in certain conditions of FMF. Occasionally we enrich published data with our own experience. To facilitate insights to anakinra role, the paper briefs some clinical, genetic, pathogenetic, and management aspects of FMF. The clinical settings of FMF covered in this review include colchicine resistance, AA amyloidosis, renal transplantation, protracted febrile myalgia, on- demand use, leg pain, arthritis, temporary suspension of colchicine, pediatric patients, and pregnancy and lactation. In many of these instances, either because of safety concerns or a necessity for only transient and short-term use, anakinra, due to its short half-life, is the preferred IL-1 blocker.

Complex immune deregulation in severe COVID-19: More than a mechanism of pathogenesis.

Complex immune deregulation in severe COVID-19: More than a mechanism of pathogenesis.

IL-10 receptor blockade controls the in vitro infectivity of Leishmania infantum and promotes a Th1 activation in PBMC of dogs with visceral leishmaniasis

An important strategy to reduce the risk of visceral leishmaniasis (VL) in humans is to control the infection and disease progression in dogs, the domestic reservoir of Leishmania infantum parasites. Certain therapeutic strategies that modulate the host immune response show great potential for the treatment of experimental VL, restoring the impaired effector functions or decreasing host excessive responses. It is known that the overproduction of interleukin-10 (IL-10) promotes parasite replication and disease progression in human VL as well as in canine visceral leishmaniasis (CVL). Thus, in the present study we investigated the potential of the anti-canine IL-10 receptor-blocking monoclonal antibody (Bloq IL-10R) to control and reduce in vitro infectivity of L. infantum and improve the ability of PBMC isolated from VL dogs to alter the lymphoproliferative response and intracytoplasmic cytokines. Overall, GFP+Leishmania showed lower capacity of in vitro infectivity in the presence of Bloq IL-10R. Moreover, addition of Bloq IL-10R in cultured PBMC enhanced T-CD4 and CD8 proliferative response and altered the intracytoplasmic cytokine synthesis, reducing CD4+IL-4+ cells and increasing CD8+IFN-γ+ cells after specific antigen stimulation in PBMC of dogs. Furthermore, we observed an increase of TNF-α levels in supernatant of cultured PBMC under IL-10R neutralizing conditions. Together, our findings are encouraging and reaffirm an important factor that could influence the effectiveness of immune modulation in dogs with VL and suggest that blocking IL-10R activity has the potential to be a useful approach to CVL treatment.

Membranous nephropathy associated with multicentric Castleman\u2019s disease that was successfully treated with tocilizumab: a case report and review of the literature

BackgroundMulticentric Castleman’s disease is a life-threatening disorder involving a systemic inflammatory response and multiple organ failure caused by the overproduction of interleukin-6. Although renal complications of Castleman’s disease include AA amyloidosis, thrombotic microangiopathy, and membranoproliferative glomerulonephritis, membranous nephropathy is relatively rare. We experienced a case of secondary membranous nephropathy associated with Castleman’s disease.Case presentationThe patient was a 43-year-old Japanese man who had shown a high zinc sulfate value in turbidity test, polyclonal hypergammaglobulinemia, anemia, and proteinuria. A physical examination revealed diffuse lymphadenopathy, an enlarged spleen and papulae of the body trunk. A skin biopsy of a papule on the patient’s back showed plasma cells in the perivascular area and he was diagnosed with multicentric Castleman’s disease, plasma cell variant. Kidney biopsy showed the appearance of bubbling in the glomerular basement membranes in Periodic acid methenamine silver stain and electron microscopy revealed electron dense deposits within and outside the glomerular basement membranes. Since immunofluorescence study showed predominant granular deposition of IgG1 and IgG2, he was diagnosed with secondary membranous nephropathy associated with Castleman’s disease. He was initially treated with prednisolone alone, however his biochemical abnormalities did not improve. After intravenous tocilizumab (700 mg every 2 weeks) was started, his C-reactive protein elevation, anemia, and polyclonal gammopathy improved. Furthermore, his urinary protein level declined from 1.58 g/gCr to 0.13 g/gCr. The prednisolone dose was gradually tapered, then discontinued. He has been stable without a recurrence of proteinuria for more than 6 months.ConclusionsTocilizumab might be a treatment option for secondary membranous nephropathy associated with Castleman’s disease.

The effect of apis Dorsata honey as a complementary therapy to interleukin-6 (IL-6) levels and T lymphocytes of post-chemotherapy breast cancer patients.

The overproduction of interleukin-6 (IL-6) in breast cancer cases can aggravate metastases. In comparison, the production of T lymphocytes plays a role in suppressing the development of tumor cells. Honey as a complementary therapy is expected to reduce the overproduction of IL-6 and facilitate the production of T lymphocytes in breast cancer cases. This study aims to determine the effect of Dorsata honey (DH) as a complementary therapy to IL-6 levels and T lymphocytes of post-chemotherapy in breast cancer. This study was a quasi-experimental approach that employed a pretest-posttest group control design. As many as 30 post-chemotherapy breast cancer patients at the Central Hospital in Eastern Indonesia were randomly selected into a control group of 15 participants. Additionally, an intervention group of 15 participants was given DH orally three times a day at a dose of 15ml. The blood sample was taken two times, day 0 of the chemotherapy and day 16 (post-chemotherapy). The level of IL-6 was measured by ELISA, while the data were analyzed by Wilcoxon, independent T-test, and Mann-Whitney test. The results showed that DH did not significantly affect IL-6 levels (p = 0.17). However, there was an increase in T lymphocyte levels with statistically significant differences (p = 0.01) in intervention groups. There was no difference in Il-6 and T lymphocyte levels between the intervention and control groups (p > 0.05). Il-6 levels tend to be constant in the intervention group. However, there is a significant increase in the T lymphocyte levels which can indirectly increase the immune system and inhibit tumor cell growth in patients with breast cancer.

The Effect of Hexabromocyclododecane on the Production of Interleukin‐6 by Human Immune Cells

Hexabromocyclododecane (HBCD) is a compound that is used as an additive flame retardant for thermal insulation in buildings, but it can also be used in this manner for furniture fabrics and electrical apparatuses. Due to its hydrophobic properties it can leach from products such as treated fabrics and insulating materials and is found in dust particles, soil, and sewage sludge. This environmental contamination has led to its presence and in a number of foods especially fatty seafood, but also nuts and nut butters. HBCD has been detected in human serum samples. Possible routes for this exposure and accumulation of HBCD in human tissue could be due to exposure to HBCD treated products, dust particles, and ingestion of contaminated foods. Interleukin- 6 (IL-6) is produced by a number of different cell types, including human immune cells. It is involved in cell proliferation, differentiation, apoptosis, and bone remodeling. When IL-6 is overproduced it can lead to chronic inflammation. Diseases such as Castleman disease, Crohn's disease, rheumatoid arthritis, juvenile idiopathic arthritis, bone loss, and cardiovascular disease are associated with overproduction of IL-6. HBCD has been shown to increase the secretion of other pro-inflammatory cytokines. We hypothesize that HBCD may also increase production of IL-6. In this study peripheral blood mononuclear cells (PBMCs) were isolated from leukocyte filters and then exposed to HBCD for 24 hours at different concentrations (5-0.05 μM). Production of IL-6 (combination of secreted and intracellular levels) was determined by measuring secreted levels via enzyme linked immunosorbent assay (ELISA) and intracellular levels via Western blot. Increases in production of IL-6 were seen at five or more of the HBCD exposure levels in cells from 5 different donors. The average increase in IL-6 production seen at the 1 µM exposure was 2.4 fold (ranging from 1.2-3.6 fold) while that at 0.1 µM was 2.2 fold (ranging from 1.2-2.8 fold). These results show thatHBCD can induce increases in production of IL-6. Thus, HBCD may have the potential to contribute to inflammation in exposed individuals.

Interleukin-6 producing pheochromocytoma/paraganglioma: case series from a tertiary referral centre for pheochromocytomas and paragangliomas

IntroductionIn addition to catecholamines, pheochromocytomas and paragangliomas (PPGL) may secrete interleukin-6 (IL-6). IL-6 contributes to the development of unusual symptoms, which may hinder the diagnosis. Patients and methodsWe report the clinical course and subsequent treatment of IL-6 producing PPGL in three patients from a single tertiary referral centre for PPGL patients in the Netherlands.Conclusion PPGL combined with persistent elevated inflammatory markers, either in the presence or absence of pyrexia, raised suspicion of IL-6 overproduction in these three patients. Although surgical resection of the tumour is the only curative treatment option, our case series adds to the accumulating evidence that alpha-blockers might be effective in these patients.

Agomelatine effects on fat-enriched diet induced neuroinflammation and depression-like behavior in rats

Growing evidence suggests that a high fat diet (HFD) induces oxidative stress on the central nervous system (CNS), which predisposes to mood disorders and neuroinflammation. In this study we postulated that in addition to improving mood, antidepressant therapy would reverse inflammatory changes in the brain of rats exposed to a HFD. To test our hypothesis, we measured the effect of the antidepressant agomelatine (AGO) on anxiety- and depressive-like behaviors, as well as on CNS markers of inflammation in rats rendered obese. Agomelatine is an agonist of the melatonin receptors MT1 and MT2 and an antagonist of the serotonin receptors 5HT2B and 5HT2C. A subset of rats was also treated with lipopolysaccharides (LPS) to determine how additional neuroinflammation alters behavior and affects the response to the antidepressant.Specifically, rats were subjected to a 14-week HFD, during which time behavior was evaluated twice, first at the 10th week prior to LPS and/or agomelatine, and then at the 14th week after a bi-weekly exposure to LPS (250 μg/kg) and daily treatment with agomelatine (40 mg/kg). Immediately after the second behavioral testing we measured the proinflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and interleukin 1 beta (IL-1β), markers of oxidative stress thiobarbituric acid reactive substances (TABRS), catalase (CAT) and glutathione peroxidase (GPx), the growth factor BDNF, as well as the apoptosis marker caspase-3.Our results show that a HFD induced an anxiety-like behavior in the open field test (OFT) at the 10th week, followed by a depressive-like behavior in the forced swim test (FST) at the 14th week. In the prefrontal and hippocampal cortices of rats exposed to a HFD we noted an overproduction of TNF-α, IL-6, IL-1β, and TABRS, together with an increase in caspase-3 activity. We also observed a decrease in BDNF, as well as reduced CAT and GPx activity in the same brain areas.Treatment with agomelatine reversed the signs of anxiety and depression, and decreased the cytokines (TNF-α, IL-6 and IL-1β), TABRS, as well as caspase-3 activity. Agomelatine also restored BDNF levels and the activity of antioxidant enzymes CAT and GPx.Our findings suggest that the anxiolytic/antidepressant effect of agomelatine in obese rats could result from a reversal of the inflammatory and oxidative stress brought about by their diet.