Interleukin 6

Functions of hematopoietic stem cells (HSCs) are tightly regulated to ensure lifelong normal hematopoiesis within the bone marrow (BM) niche. While HSCs' status is well orchestrated to uphold their stemness, the fate of HSCs can be altered in response to inflammatory signals caused by environmental changes. The influence on HSCs of inflammatory changes within BM has been explored; however, how each inflammatory cytokine affects the maintenance or differentiation of HSCs remains to be fully elucidated. Considering recent studies demonstrating that reactive oxygen species (ROS) influence HSCs' fates, we conducted a comprehensive analysis of the effects of seven major inflammatory cytokines on proliferation, differentiation, and ROS level regulation in HSCs / hematopoietic stem/progenitor cells (HSPCs). Our study indicates that inflammatory cytokines in general push HSCs/HSPCs into differentiation, but vary significantly with respect to retention of primitive cells. With definition by cellular immunophenotypes, TNF-α, IFN-γ, and type I IFNs stimulated loss of HSCs, whereas TGF-β and IL-6, and possibly IL-1β as well, showed potential to retain them. Of note is that unaltered ROS levels were compatible with HSC retention, while drastic change, either increase or decrease, in ROS levels presaged HSC loss. Detailed evaluation of links between inflammatory cytokines and ROS regulation appears likely to prove important in understanding HSC biology and translating basic science into clinical applications.

Importance  Olfaction is a complex sensory process that has not been fully studied. Elevated plasma levels of interleukin 6 (IL-6) have been found in patients with several acute and chronic diseases but have not been reported in patients with smell loss (hyposmia).

Objective  To determine IL-6 levels in patients with hyposmia.

Design  Retrospective study. All measurements were made without reference to the origin of any collected sample.

Setting  An ambulatory private practice at The Taste and Smell Clinic in Washington, DC.

Participants  Fifty-nine consecutive patients who presented to the clinic between 2005 and 2008 for evaluation and treatment of various degrees of hyposmia were studied. Nine volunteers with normal sensory function served as controls.

Main Outcomes and Measures  Levels of IL-6 were measured in samples of plasma, urine, saliva, and nasal mucus.

Results  All biological fluid samples studied contained IL-6. Mean (SEM) levels in plasma, saliva, and nasal mucus in patients were significantly higher than in controls (0.95 [0.10] vs 0.12 [0.03] pg/mL, 0.57 [0.05] vs 0.30 [0.01] pg/mL, and 29.7 [3.8] vs 11.6 [0.5] pg/mL, respectively; all P < .001). The concentration of IL-6 in nasal mucus in patients was significantly higher than in controls and was more than 30 times higher than in any other biological fluid. Mean (SEM) levels in urine were not significantly different: 0.92 (0.17) pg/mL for patients and 1.26 (0.41) pg/mL for controls (P > .50).

Conclusions and Relevance  Compared with controls, IL-6 in patients was significantly elevated in plasma, saliva, and nasal mucus. Because IL-6 is a proinflammatory cytokine, these changes can relate to local or systemic inflammatory processes, which can be a cause or a result of pathological processes associated with hyposmia. These results support the concept that hyposmia has a biochemical basis and IL-6 may play a role in biochemical pathological processes underlying hyposmia and its treatment.

Loss of smell (hyposmia) is a symptom reflective of multiple chronic disease processes involving multiple organ systems and somatic processes including endocrine, vitamin, trace metal, metabolic, neurological, neurodegenerative, hematological, immunological, and other organ systems and processes. Hyposmia can reflect local changes in the oral or nasal cavities affecting olfactory receptors, in the nerves connecting receptors to the brain, or in the brain itself. The systemic changes associated with these major pathological processes include hyposmia as a major symptom. Descriptions of hyposmia associated with these pathological processes have been made by many prior investigators.

We have attempted to understand the changes in secretions of the multiple organ systems in the multiple pathological processes responsible for initiation and perpetuation of hyposmia. Thus, we have reported that decreases in specific biochemical moieties are associated with hyposmia onset and that their replacement has corrected this symptom. For example, lack of thyroid hormone induces hypothyroidism with its associated systemic symptoms, one of which is hyposmia; administration of thyroid hormone corrects the systemic symptoms of hypothyroidism and the associated hyposmia. Zinc deficiency induces multiple systemic symptoms and hyposmia, which is manifested by decreased gustin (carbonic anhydrase VI) secretion; administration of zinc ion supplementation to these patients corrects both these systemic symptoms and the associated hyposmia, this latter effect being associated with the zinc-induced increase in carbonic anhydrase VI secretion. The multiple biochemical moieties of these diverse organ systems that correct hyposmia in these various pathological processes have been determined to be growth factors that stimulate olfactory epithelial stem cells to initiate maturation and renewal of the sensory cells responsible for normal olfaction.

Olfaction is a complex process comprising multiple components including receptors, nerves, and brain. The local and systemic components of this complex process have not been fully explored. Cell-signaling processes are critical in any complex sensory system such as olfaction, and we and others have investigated several aspects of these signaling processes, some involving adenylyl cyclases, sonic hedgehog, and some cytokines. Among these cytokines, we were interested in determining levels of interleukin 6 (IL-6) in patients with hyposmia because no prior studies of this type among these patients have been reported.

It is well known that IL-6, a proinflammatory cytokine, is overproduced in a spectrum of clinical illnesses and conditions including cardiovascular disease, osteoporosis, arthritis, type 2 diabetes mellitus, renal disease, hepatitis, schizophrenia, preeclampsia, various neoplasms, periodontal disease, frailty, stress, and functional decline. Increased IL-6 level has been reported in these conditions, mainly in blood plasma. Increased IL-6 level has been reported in both plasma and ventricular fluid following acute but not chronic head injury. Increased IL-6 level has been reported in cerebrospinal fluid following traumatic brain injury and to trigger nerve growth factor secretion in astrocytes. Increased IL-6 level has been reported in blood plasma of patients with persistent sciatic pain, and IL-6 mRNA level has been reported increased in rat spinal cord following peripheral nerve injury. Increased IL-6 level has been reported in plasma and in saliva of some patients with burning mouth syndrome (BMS) but not in others; no IL-6 differences were reported in these patients with and without associated depression and perceived pain. However, stress hormones have been reported to regulate IL-6 expression in various ovarian carcinoma cells through a Src-dependent mechanism. These results suggest that both specific and nonspecific factors elicit changes in IL-6 in several biological fluids in several disease processes including neurological, inflammatory, and psychological stress.

To evaluate IL-6 in patients with hyposmia, we undertook an investigation of IL-6 levels in samples of plasma, urine, parotid saliva, and nasal mucus obtained from patients with hyposmia and compared these levels with similar measurements obtained in a group of controls. We previously published a preliminary study of some of these results, and we now present a comprehensive study.

Interleukin (IL)-1 beta and IL-6 levels in plasma and cerebrospinal fluid (CSF) of 14 medicated schizophrenic patients and 9 controls were measured by enzyme-linked immunosorbent assay. Almost no detectable levels of IL-6 in plasma or CSF from patients or controls were found. With regard to mean plasma or CSF levels of IL-1 beta there were no statistically significant differences between the two groups investigated. The dose of neuroleptic medication the patients used did not correlate with the IL-1 beta plasma levels. For the whole series of subjects (n = 23) or for the schizophrenic patients (n = 14) no correlation between the plasma and CSF levels of IL-1 beta was found.

The spike glycoprotein of the SARS-CoV-2 virus, which causes COVID-19, has attracted attention for its vaccine potential and binding capacity to host cell surface receptors. Much of this research focus has centered on the ectodomain of the spike protein. The ectodomain is anchored to a transmembrane region, followed by a cytoplasmic tail. Here we report a distant sequence similarity between the cysteine-rich cytoplasmic tail of the coronavirus spike protein and the hepcidin protein that is found in humans and other vertebrates. Hepcidin is thought to be the key regulator of iron metabolism in humans through its inhibition of the iron-exporting protein ferroportin. An implication of this preliminary observation is to suggest a potential route of investigation in the coronavirus research field making use of an already-established literature on the interplay of local and systemic iron regulation, cytokine-mediated inflammatory processes, respiratory infections and the hepcidin protein. The question of possible homology and an evolutionary connection between the viral spike protein and hepcidin is not assessed in this report, but some scenarios for its study are discussed.

Background:There is widediversityofbiochemical componentsofthehumansalivathismakesit suitabletobeusedasabiological fluidofdiagnosticvalue. Anychange of biochemicalsofthesalivacouldberelatedtoperiodontaldiseases.,,salivacanprovidedifferent advantages, includingeasycollectionandnon-invasivesamplingmethod when it usedasa diagnosticmaterial.Cytokinesarepivotaltothepathogenesisofperiodontaldiseaseandmaybeusedasmarkersin diagnosis.Proinflammatory cytokines aremediatorscloselyassociated with the pathogenesis of periodontitis.In saliva ofthe patientswith chronicperiodontitis,the levels ofseveral interleukins were increased.Numerous cytokines have been identified at sites of chronic inflammation such as periodontitis. One of these, is interleukin-6 (IL-6), whichis a major mediator of host response to infection and tissue injury. IL-6 plays a major role in B cell differentiationand alsopromotes T cell proliferation and bone resorption. Subjects and methods:Inthepresentstudyone hundred and one (101)males p a t i e n t s wereenrolledwithanagerangingfrom(35-55)years.Thesample weredividedinto three maingroups (30) healthycontrol patient,(30) patients with gingivitis,,and (41)patientshavechronicperiodontitis Allwere from attendantstoDepartmentofPeriodontics,School ofDentistry,UniversitySulaimani.Allsubjectswere in good general health and had not received previous periodontal therapy or taken antibiotics,oranti-inflammatorydrugsinthethree monthsbeforethestudy .The ClinicalPeriodontalParameters include Plaqueindex(PLI) ,GingivalIndex(GI) , BleedingonProbing(BOP), ProbingPocketDepth(PPD)and Clinical attachment level (CAL) .Saliva was collected for five minutes (5-10 ml) from each patient into asteriletube. Saliva was immediately centrifuged at 3500 rpm for ten minutes and stored at −20°C ,until analysis by Cobas E analyzer(Roche made in Germany) for detectionofInterleukin 6 (IL-6)). ConcentrationsoftheInterleukin 6 (IL-6) in s a l i v a measuredin(pg/µl.) Results:Theconcentration of interleukin-6 (IL-6) (pg/µl) insalivawas higher in chronic periodontitis group (13.4pg/µl))thaningingivitis(7.5pg/µl) andincontrolgroup(5.27 pg/µl).There was high significant differences among concentration of IL-6(pg/µl) among the three groups P-value(0.000). The mean pocket depth in chronic periodontitis group (5.48. ±1.64) and the mean of clinical attachment loss (3.26 , ± 1.49). There were high significant difference between chronic periodontitis , gingivitis and control group in clinical parameters [Plaqueindex(PLI) ,GingivalIndex(GI) , BleedingonProbing(BOP), ProbingPocketdepth(PPD)] p-value (0.000) Conclusion:Theconcentration of interleukin-6 (IL-6) (pg/µl) insalivawashigherin chronicperiodontitisgroupthaningingivitisgroupandincontrolgroupand IL-6canberegardasdiagnostic markerwhichgiveinformationabout progression ofperiodontaldisease.

Abstract
BACKGROUND:
Episodic bouts of abdominal pain and altered bowel habit are characteristic of irritable bowel syndrome (IBS). Although a comprehensive understanding of IBS pathophysiology remains elusive, support is growing for a primary role for immune activation in disease severity as evidenced by altered cytokine profiles in IBS plasma. Additionally, aberrant stimulation of the stress axis is likely to result in altered plasma constituents.
METHODS:
Whole-mount preparations of submucosal plexus from adult male Sprague Dawley rats were exposed to plasma from IBS patients and healthy controls. Ratiometric calcium imaging recordings were used to measure changes in intracellular calcium ([Ca(2+)]i) as a marker of neuronal excitability.
KEY RESULTS:
IBS plasma stimulated a robust increase in [Ca(2+)]i (0.09 ± 0.02) whereas plasma from healthy volunteers had little effect (-0.02 ± 0.02, n=24, p<0.001). The neuromodulatory actions of IBS plasma were reduced by pre-neutralisation with anti-interleukin (IL)-6 (p<0.01) but not IL-8, immunoglobulin G or C-reactive protein. Moreover, IBS plasma-evoked responses (0.22 ± 0.06) were inhibited by the corticotrophin releasing factor receptor (CRFR) 1 antagonist, antalarmin (1μM, 0.015 ± 0.02, n=14, p<0.05), but not the CRFR2 antagonist, astressin 2B. Neuronal activation was mediated by ERK/MAPK signalling.
CONCLUSIONS:
These data provide evidence that factors present in IBS plasma modulate neuronal activity in the submucosal plexus and that this is likely to involve CRFR1 activation and IL-6 signalling. These neuromodulatory actions of stress and immune factors indicate a potential mechanism by which immune activation during periods of stress may lead to symptom flares in IBS.

Aim: The study determined the effect of ascorbic acid (administered orally and intramuscularly) in short-term transportation stress.

Materials and Methods: Twenty-four apparently healthy Kalahari goats were grouped into four groups (A, B, C, and D) of 6 animals each: Group A - untreated and unexposed to stress; Group B - treated with 200 mg/kg Vitamin C orally and exposed to 2 h transportation stress; Group C - treated with Vitamin C 200 mg/kg intramuscularly and exposed to 2 h transportation stress; and Group D - untreated and exposed to 2 h transportation stress. The animals were stocked using standards stipulated by the Nigerian Animal Disease Control Act and transported at 40 km/h. Cortisol and interleukin-6 (IL-6) were assayed using quantitative sandwich ELISA. Classical stress hematological parameters and antioxidative stress markers such as glutathione s-transferase, superoxide dismutase, and malondialdehyde were determined. Heart rate variability (HRV) was also assessed.

Results: The route of ascorbic acid administration did not influence the expression of IL-6, and changes in cortisol surge, antioxidative stress markers, and other hematological parameters in Kalahari goats though Group C goats showed higher HRV values (p<0.05) than others. This gives credence to the enhanced cardiac responsiveness and stress survivability in Kalahari goats.

Conclusion: Both routes could be used in the administration of ascorbic acid. Kalahari goats exposed to short-term stress; however, the intramuscular route had better heart variability and thus improved the survivability of the animals.

Cancer-associated fibroblasts (CAFs) secrete various pro-tumorigenic cytokines, yet the role of these cy-tokines in the progression of endometrial cancer remains unclear. We found that CAFs isolated from human endo-metrial cancer (EC) tissues secreted high levels of interleukin-6 (IL-6), which promotes EC cell proliferation in vitro. Neutralizing IL-6 in CAF-conditioned media reduced (47% inhibition) while IL-6 recombinant protein increased cell proliferation (~2.4 fold) of both EC cell lines and primary cultures. IL-6 receptors (IL-6R and gp130) were expressed only in EC epithelial cells but not in CAF, indicating a one-way paracrine signaling. In the presence of CAF-conditioned media, Janus kinase/signal transducers and activators of transcription (JAK/STAT3) pathway was activated in EC cells. Treatment with JAK and STAT3 specific inhibitors, AD412 and STATTIC, respectively, significantly abrogated CAF-mediated cell proliferation, indicating the role of IL-6 activation in EC cell proliferation. We further showed that one of STAT-3 target genes, c-Myc, was highly induced in EC cells after exposure to CAF-conditioned medium at both mRNA (>105-fold vs. control) and protein level (>2-fold vs. control). EC cell proliferation was dependent on c-Myc expression, as RNAi-mediated c-Myc down-regulation led to a significant 46% reduction in cell viability when compared with scrambled control. Interestingly, CAF-conditioned media failed to promote proliferation in EC cells with reduced c-Myc expression, suggesting that CAF-mediated cell proliferation was also dependent on c-Myc expression. Subcutaneous tumor xenograft model showed that EC cells grew at least 1.4 times larger when co-injected with CAF, when compared to those injected with EC cells alone. Mice injected with EC cells with down-regulated c-Myc expression, however, showed at least 2.5 times smaller tumor compared to those in control group. Notably, there was no increase of tumor size when co-injected with CAFs. Further immunohistochemical staining on human tissues showed positive expression of IL-6 receptors, phosphorylated-STAT3 and c-Myc in human EC tissues with less signals in benign endometrium. Taken together, our data suggests that IL-6 secreted by CAF induces c-Myc expression to promote EC proliferation in vitro and in vivo. IL-6 pathway can be a potential target to disrupt tumor-stroma interaction in endometrial cancer progression.

The article contains the information about pro- and anti-inflammatory cytokines in infants with acute obstructive bronchitis and thymus hypertrophy. The content of IL-6 and IL-10 has been determined in 101 children in acute period of disease and during early convalescence. It was found the increasing of production of proinflammatory IL-6 and a low level of anti-inflammatory IL-10 in the first days of illness in all children with thymomegalia. During convalescence in patients with acute obstructive bronchitis and thymomegalia IL-6 level was decreasing, and the level of IL-10 was increasing, but it did not amount to the level of healthy children.

Understanding the determinants of the host innate immune response to systemic administration of adenoviral (Ad) vectors is critical for clinical gene therapy. Acute toxicity occurs within minutes to hours after vector administration and is characterized by activation of innate immune responses. Our data indicate that in mice, indicators of vector toxicity include elevations of cytokine levels, liver transaminase levels and thrombocytopenia. To discern potential targets for blunting this host response, we evaluated genetic factors in the host response to systemically administered first-generation Ad vectors (FGV) and helper-dependent Ad vectors (HDV) containing beta-galactosidase expression cassettes. A preliminary screen for modulation of vector-induced thrombocytopenia revealed no role for interferon-gamma, mast cells or perforin. However, vector-induced thrombocytopenia and interleukin 6 (IL-6) expression are less evident in tumor necrosis factor alpha (TNFalpha)-deficient mice. Moreover, we also demonstrated that TNFalpha blockade via antibody or huTNFR:Fc pretreatment attenuates both thrombocytopenia (>40% increase in platelet count) and IL-6 expression (>80% reduction) without affecting interleukin 12 , liver enzymes, hematological indices or vector transduction in a murine model. Our data indicate that the use of HDV, in combination with clinically approved TNFalpha immunomodulation, may represent an approach for improving the therapeutic index of Ad gene therapy for human clinical trials.

Even though it has been well documented that stress can lead to the development of sleep disorders and the intensification of pain, their relationships have not been fully understood. The present study was aimed at investigating the effects of predictable chronic mild stress (PCMS) on sleep-wake states and pain threshold, using the PCMS rearing conditions of mesh wire (MW) and water (W) for 21 days. Exposure to PCMS decreased the amount of non-rapid eye movement (NREM) sleep during the dark phase. Moreover, the chronicity of PCMS decreased slow-wave activity (SWA) during NREM sleep in the MW and W groups in both the light and dark phases. Mechanical and aversively hot thermal hyperalgesia were more intensified in the PCMS groups than the control. Higher plasma corticosterone levels were seen in mice subjected to PCMS, whereas TNF-α expression was found higher in the hypothalamus in the W and the trigeminal ganglion in the MW group. The W group had higher expression levels of IL-6 in the thalamus as well. The PCMS paradigm decreased SWA and may have intensified mechanical and thermal hyperalgesia. The current study also suggests that rearing under PCMS may cause impaired sleep quality and heightened pain sensation to painful mechanical and aversively hot thermal stimuli.

BACKGROUND: Postoperative serum inflammatory cytokine levels are thought to reflect the magnitude of surgical stress. Cytokine interleukin-6 (IL-6) is an early marker of systemic inflammatory response and tissue damage. This study evaluated levels of IL-6 after open and laparoscopic appendectomy to compare the degree of surgical stress associated with these procedures.

Conclusion: A high serum IL-6 expression is associated with adverse OS in CRC. The IL-6 expression can be an important supplement in establishing prognostic score for clinical decision.

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We quantitated interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R) and soluble form of the IL-6 signal-transducing protein gp130
(sgp130) in cerebrospinal fluid (CSF) of patients with Alzheimer’s disease (AD) (n = 17) and control subjects (n = 18) using
sensitive enzyme-linked immunosorbent assays (ELISA). Our results show that none of the parameters examined was significantly different in CSF of AD patients as compared to control age-matched non-demented patients. We conclude that CSF levels of IL-6 and their soluble receptors do not necessarily reflect local changes of the IL-6 system that has been shown to be involved in neurodegenerative events occurring in AD. Levels of sgp130 are substantially high (approximately 100 ng/ml) in the CSF of all individuals probably representing a high antagonistic potential.

Cardiac myofibroblasts (CMF) play a key role in infarct repair and scar formation following myocardial infarction (MI) and are also an important source of proinflammatory cytokines. We postulated that interleukin-1alpha (IL-1alpha), a potential early trigger of acute inflammation post-MI, could stimulate human CMF to express additional proinflammatory cytokines. Furthermore, we hypothesized that these effects may be modulated by the anti-inflammatory cytokine interleukin-10 (IL-10). Human CMF were cultured from atrial biopsies from multiple patients. Interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and cardiotrophin-1 (CT-1) mRNA expression and secretion were measured using quantitative real-time RT-PCR and enzyme-linked immunosorbent assay. IL-1alpha (0.001-10 ng/ml, 0-6 h) stimulated IL-1beta, TNF-alpha, and IL-6 mRNA expression with distinct temporal and concentration profiles, resulting in increased cytokine secretion. The response to IL-1alpha was much greater than with TNF-alpha. Neither IL-1alpha nor TNF-alpha treatment modulated CT-1 mRNA expression. Immunoblotting with phosphospecific antibodies revealed that IL-1alpha stimulated the extracellular signal-regulated kinase (ERK)-1/2, p38 mitogen-activated protein kinase (MAPK), c-Jun NH(2)-terminal kinase (JNK), phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B (Akt), and nuclear factor (NF)-kappaB signaling pathways. Pharmacological inhibitor studies indicated roles for PI 3-kinase/Akt and NF-kappaB pathways in mediating IL-1beta expression, and for NF-kappaB and p38 MAPK pathways in mediating TNF-alpha expression. IL-1alpha-induced IL-6 mRNA expression was reduced by p38 MAPK inhibition, but increased by ERK and JNK pathway inhibitors. IL-10 produced a consistent but modest reduction in IL-1alpha-induced IL-6 mRNA levels (not IL-1beta or TNF-alpha), but this was not reflected by reduced IL-6 protein secretion. In conclusion, IL-1alpha stimulates human CMF to express IL-1beta, TNF-alpha, and IL-6 via specific signaling pathways, responses that are unaffected by IL-10 exposure.

Objective
Epilepsy is accompanied by inflammation, and the anti-inflammatory agents may have anti-seizure effects. In this investigation, the effect of deep brain stimulation, as a potential therapeutic approach in epileptic patients, was investigated on seizure-induced inflammatory factors.

Materials And Methods
In the present experimental study, rats were kindled by chronic administration of pentylenetetrazol (PTZ; 34 mg/Kg). The animals were divided into intact, sham, low-frequency deep brain stimulation (LFS), kindled, and kindled +LFS groups. In kindled+LFS and LFS groups, animals received four trains of intra-hippocampal low-frequency deep brain stimulation (LFS) at 20 minutes, 6, 24, and 30 hours after the last PTZ injection. Each train of LFS contained 200 pulses at 1 Hz, 200 µA, and 0.1 ms pulse width. One week after the last PTZ injection, the Y-maze test was run, and then the rats’ brains were removed, and hippocampal samples were extracted for molecular assessments. The gene expression of two pro-inflammatory factors [interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α)], and glial fibrillary acidic protein (GFAP) immunoreactivity (as a biological marker of astrocytes reactivation) were evaluated.

Results
Obtained results showed a significant increase in the expression of of interleukin-6 (IL-6), tumor necrosis factor (TNF)-α, and GFAP at one-week post kindling seizures. The application of LFS had a long-lasting effect and restored all of the measured changes toward normal values. These effects were gone along with the LFS improving the effect on working memory in kindled animals.

Conclusion
The anti-inflammatory action of LFS may have a role in its long-lasting improving effects on seizure-induced cognitive disorders.

BACKGROUND: Postoperative serum inflammatory cytokine levels are thought to reflect the magnitude of surgical stress. Cytokine interleukin-6 (IL-6) is an early marker of systemic inflammatory response and tissue damage. This study evaluated levels of IL-6 after open and laparoscopic appendectomy to compare the degree of surgical stress associated with these procedures.

Regardless of abundant efforts to enhance primary prevention and early detection, the number of melanoma cases in the United States has increased steadily over the past 15 years, thus greatly affecting public health and the economy. In previous studies, we demonstrated protein kinase C-ι (PKC-ι) to be an oncogene in melanoma, which promotes the activation of nuclear factor (NF)-κB, thereby supporting survival and progression. In addition, we demonstrated that PKC-ι induced the metastasis of melanoma cells by activating Vimentin, and PKC-ι inhibition downregulated epithilial-mesencymal transition (EMT), while inducing apoptosis. Of note, PKC-ι specific inhibitors downregulated the expression of both PKC-ι and phosphorylated PKC-ι, suggesting that PKC-ι plays a role in regulating its own expression in melanoma. In this study, we report the underlaying mechanisms of the transcriptional regulation of PKC-ι (PRKCI gene) expression in melanoma. c-Jun, interferon-stimulated gene factor 3 (ISGF3), paired box gene 3 (PAX3), early growth response protein 1 (EGR1) and Forkhead box protein O1 (FOXO1), which bind on or near the promoter sequence of the PRKCI gene, were analyzed for their role in PKC-ι regulation in SK-MEL-2 and MeWo cell lines. We silenced selected transcription factors using siRNA, and the results revealed that the silencing of c-Jun and FOXO1 significantly altered the expression of PRKCI. The levels of both phosphorylated and total PKC-ι increased upon FOXO1 silencing and decreased upon c-Jun silencing, suggesting that c-Jun acts as an upregulator, while FOXO1 acts as a down-regulator of PRKCI expression. We also used a multiplex ELISA to analyze multiple pathways other than NF-κB that were affected by treatment with PKC-ι inhibitor. The silencing of NF-κB p65 and PKC-ι by siRNA suggested that the regulation of PKC-ι expression was strongly associated with FOXO1. In addition, we observed a significant decrease in the mRNA levels of both interleukin (IL)-6 and IL-8, with a significant increase in the levels of IL-17E and intercellular adhesion molecule 1 (ICAM-1) upon the knockdown of expression of PKC-ι in both cell lines. This suggested that PKC-ι expression was affected by these cytokines in an autocrine manner. Overall, the findings of this study suggest that PKC-ι inhibition suppresses its own expression, diminishing oncogenic signaling, while upregulating anti-tumor signaling, thus rendering it an effective novel biomarker for use in the design of novel targeted therapeutics for melanoma.

The objective of the present study is to determine whether the levels of endogenous estrogen and interleukin-6 (IL-6) are associated with osteoarthritis (OA) in postmenopausal women. Forty-three patients who were suffering from osteoarthritis were studied and twenty control normal subjects having no symptoms of osteoarthritis disease, were also included in the study. The estrogen hormone and interleukin-6 were measured in the serum by Enzyme linked immunosorbent assay technique. Interleukin-6 and estrogen both were detected in serum. In osteoarthritis patients IL-6 levels were high as compared to control subjects (P<0.001) and estrogen levels in OA postmenopausal females was decreased significantly (p<0.01) when compared with control subjects. There was a minimal inverse correlation between IL-6 and estrogen (P<0.05) in the sera of postmenopausal osteoarthritic women. These results indicate that estrogen deficiency after menopause may cause alterations of IL-6 in postmenopausal osteoarthritic patients.

Introduction: Chronic periodontitis (CP) is an inflammatory disease caused by the interaction among dental plaque, periodontal tissues, and host immune responses, which causes bone resorption. Interleukin-6 (IL-6) and matrix metalloproteinase-1 (MMP-1) plays an important role
in the periodontium destruction. Some authors have studied polymorphisms in these genes but the results were controversial.
Objective: The aim of this study was to evaluate the association of polymorphisms in the promoter region of genes IL-6 (-174) and MMP-1 (-1607) with CP in a Northeastern Brazilian population.
Methods: A case-control study of 64 cases of CP patients and 25 healthy subjects was performed. Genomic DNA was isolated from buccal mucosa and two single nucleotide polymorphism in IL-6 (-174 G/C) and MMP-1 (-1607 1G/2G) genes were analyzed using polymerase chain reaction followed by restriction fragment length polymorphism analysis (PCR-RFLP).
Results: Regarding to results, there were no statistically significant differences between patients with CP and control group, nor to genotypes (p=0.734) nor to alleles (p=0.763), with respect to IL-6 polymorphism. For MMP-1 polymorphism, also we found no statistically significant difference in genotype (p=0.607) and allele (p=0.237) distribution between individuals with CP and the control group.
Conclusion: We concluded that the polymorphism of the studied genes were not associated with susceptibility to CP in this Northeastern Brazilian population.

Interleukins are proteins involved in the immune system and have been related to the endocrine regulation of the hypothalamic-pituitary-adrenal axis as well as to the secretion of ACTH, prolactin (PRL), GH and, possibly, LH. Like interleukin-6 (IL-6), vasoactive intestinal peptide (VIP) is synthesized in the pituitary gland and stimulates prolactin secretion. The aim of the present study was to address whether Interleukin 6 is involved in the regulation of VIP, as well as other factors involved in the regulation of prolactin such as dopamine, TRH and estradiol. Accordingly, we performed an in vitro study on monolayer cultures of rat pituitary cells, neutralizing the possible paracrine effect of IL-6 by immunosuppressing the protein by treatment with polyclonal antibody against IL-6 over 1, 3, 6 or 24 hours and then determining the degree of proliferation of VIP cells using double immunocytochemical labelling for VIP or PRL and proliferating cell nuclear antigen (PCNA). As a control, the effects of immunosuppression on the proliferation of PRL-positive cells were analyzed. Immunosuppression of IL-6 induced modifications in the cellular and nuclear size of VIP-positive cells, indicating an inhibitory process. Moreover, immunosuppression induced a significant decrease in the proliferation rate of PRL-positive or VIP-positive cells for all time-points analyzed. Similar effects on the proliferation rate of PRL-positive cells were found. The results of the present study demonstrate that IL-6 is involved in the regulation of the activity and proliferation of pituitary VIP-producing cells and suggest that, without ruling out a direct effect of IL-6 on prolactin cells, IL-6 could regulate prolactin by acting on pituitary VIP.

Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) have been linked to prenatal risk factors including maternal obesity, stress, and viral infections during pregnancy. These risk factors share a common mechanism, elevated inflammatory cytokines and in particular, elevated interleukin-6 (IL-6). Resting state functional connectivity (rs-fcMRI) abnormalities have been identified in both ADHD and ASD and have similarly been identified in infants whose mothers had elevated IL-6 blood levels. The current work uses a rodent model to test the causal mechanisms of IL-6 exposure and behavioral and neural phenotypes associated with these developmental disorders. Sprague-Dawley rats were implanted with osmotic pumps delivering either saline or a daily dose of 4.98 ug/kg IL-6 over the course of 40 days. This dose was designed to mimic chronic inflammatory states throughout pregnancy. Offspring were given a battery of behavioral tests and rsfc-MRI imaging both early (PD25) and late (PD50) in development. Here, we find that IL-6 exposed offspring show a robust anxiety phenotype on both the open field and light dark behavioral tests. We also found that IL-6 animals more readily acquired fear, as measured by increased freezing to three 0.5 mV footshocks. No differences in social approach behavior was found. Finally, to serve as a translational tool, we discuss atypical network structure, default mode network connectivity in IL-6 exposed animals, and the relationship of these findings to connectivity structure seen in developmental disorders. Overall, this work sheds light on the underlying mechanisms associated with maternal inflammation and the role of IL-6 as a risk factor for developing phenotypes seen in ASD and ADHD.

Although the most notable clinical symptoms of Huntington’s disease (HD) are motor disturbances and brain atrophy, other symptoms include cognitive dysfunction, emotional and hormonal dysregulation. Emotional dysregulation (irritability, anger/aggression, and anxiety) and increased inflammation are early emerging symptoms which can be detected decades before the onset of motor symptoms in HD patients. Despite the advances in understanding the genetic causes of HD there is still no cure or preventative treatment. Thus, to better understand the pathogenesis of HD and develop effective treatments, a holistic understanding of HD is needed, as well as animal models that replicate the full spectrum of HD symptoms. The current study examined the emotional, hormonal, and gene expression responses to an acute stressor of adult male transgenic HD rhesus monkeys (n = 2) as compared to wild-type controls (n = 2). Results revealed that HD monkeys expressed increased anxiety and irritability/aggression as compared to controls. Reactive cortisol response to the stressor was similar between groups. However, HD monkeys exhibited increased pro-inflammatory cytokines and higher induction of immune pathway genes as compared to controls. Overall, results reveal that HD monkeys exhibit these early emerging symptoms of HD and may be an effective animal model to facilitate the development of new therapeutics for HD patients.

Raper, J., et al. Increased irritability, anxiety, and immune reactivity in transgenic Huntington’s disease monkeys. Brain Behav. Immun. (2016), http://dx.doi.org/10.1016/j.bbi.2016.07.004

The pathogenesis of epizootic haemorrhagic disease (EHD) in white‑tailed deer (WTD) may be related to factors other than direct viral damage caused by replication in endothelium, such as the release of cytokines. This study focused on interleukin‑1 β (IL‑1) and interleukin‑6 (IL‑6), which have been shown to be variably upregulated in Bluetongue virus (BTV) infected cattle and sheep endothelial cultures possibly explaining species susceptibility to BTV. We evaluated circulating and tissue levels of IL‑1 and IL‑6 in WTD experimentally infected with EHD virus serotype 2 (EHDV‑2). Circulating levels of IL‑1 were assayed by ELISA. RT‑PCR and immunohistochemistry (IHC) were used to detect upregulation of IL‑1 and IL‑6 mRNA as well as protein expression, respectively. RT‑PCR was also used to determine whether IL‑1 and IL‑6 were upregulated in WTD peripheral blood mononuclear cells (PBMC) infected with EHDV‑2 in vitro. We found increased circulating levels of IL‑1 and upregulation of IL‑1 mRNA and protein expression and upregulation of IL‑6 mRNA in tissues of WTD infected with EHDV. Upregulation of mRNA levels of IL‑1 and IL‑6 in EHDV infected PBMCs was also observed. Findings suggest a role for IL‑1 and IL‑6 in the pathogenesis of EHD in WTD.

Pneumonia is an inflammatory disease and may be associated with inflammatory interleukin. In this study Interleukin-6 has been analyzed to associated with the Pneumonia. This association study was carried out on 251 case and control. 5 ml blood sample of case and control were analyzed by ELISA reader for Interleukin-6 concentration. The present study found statistically significant at the level of P<0.0001, the value of t test was t=143.2with the degree of freedom 998.

Objective(s): Bacterial infection contributes substantially to neonatal morbidity and mortality. Early diagnosis of neonatal sepsis is difficult because clinical signs are non-specific. We have evaluated serum IL-6, 8 and 10 as potential early diagnostic markers of neonatal infection and their relationship to mortality rate and poor prognosis.
Materials and Methods: A total of 84 infants, aged ≥ 72 hr were enrolled in this prospective case-control trial. The case group (n=41) included babies with clinical and laboratory findings compatible with sepsis and/or positive blood or cerebrospinal fluid cultures. The control group (n=43) included healthy infants. IL-6, 8 and 10 were measured for all infants. Receiver-operating characteristic (ROC) curves were used for the determination of thresholds.
Results: Statistically significant differences were observed between control and case groups for serum median level of IL-6, 8 and 10 (P<0.001). IL-6 cut-off values of 10.85 Pg/ml for discriminating between cases and controls and 78.2 Pg/ml for predicting mortality are suggested. IL-8 at a cut-off value of 60.05 Pg/ml was valuable for differentiation of definite versus indefinite infection.
Conclusion: Evaluating the IL-6, 8 and 10 simultaneously, could improve the sensitivity and specificity of early diagnosis of the neonatal sepsis. Regarding our results, interleukin 6 had the greatest value for predicting infection and possible mortality, whereas IL-8 was valuable for diagnosing definitive infection.

Background: Use of Carica papaya leaf extracts, reported to improve thrombocyte counts in dengue patients, demands further analysis on the underlying mechanism of its thrombopoietic cytokines induction. Methods: In vitro cultures of peripheral blood leukocytes (PBL) and stem cells from human exfoliated deciduous teeth (SHED) were treated with unripe papayapulp juice (UPJ) to evaluate its potential to induce thrombopoietic cytokines (IL-6 and SCF)  Results: In vitro scratch gap closure was significantly faster (p < .05) in SHED culture treated with UPJ. IL-6 concentration was significantly increased (p < .05) in SHED and PBL culture supernatant when treated with UPJ. SCF synthesis in SHED culture was also significantly increased (p < .05) when treated with UPJ  Conclusion: In vitro upregulated synthesis of IL-6 and SCF both in PBL and SHED reveals the potential mechanism of unripe papaya to induce thrombopoieticcytokines synthesis in cells of hematopoietic and mesenchymal origin.

Besides its wide range of action as a proinflammatory cytokine in the immune system, interleukin-6 (IL-6) has also
attracted much attention due to its influence on the nervous system. In the present study we show that the designer fusion
protein H-IL-6, consisting of IL-6 and its specific receptor IL-6R-
, but not IL-6 alone, mediates both neuro- as well as
gliogenesis. Using immunocytochemistry, Western blot, and patch-clamp recording, we demonstrate that H-IL-6 induces
the differentiation of neural stem cells (NSCs) specifically into glutamate-responsive neurons and two morphological
distinctive astroglia cell types. H-IL-6–activated neurogenesis seems to be induced by the MAPK/CREB (mitogenactivated
protein kinase/cAMP response element-binding protein) cascade, whereas gliogenesis is mediated via the
STAT-3 (signal transducers and activators of transcription protein-3) signaling pathway. Our finding that IL-6 mediates
both processes depending on its specific soluble receptor sIL-6R-
has implications for the potential treatment of
neurodegenerative diseases.

Pre-clinical studies suggest that the p38 MAPK signaling pathway plays a detrimental role in cardiac remodeling, but its role in cardiac fibroblast (CF) function is not well defined. We aimed to identify the p38 MAPK subtypes expressed by human CF, study their activation in response to proinflammatory cytokines, and determine which subtypes were important for expression of specific cytokines and matrix metalloproteinases (MMPs). Quantitative real-time RT-PCR analysis of mRNA levels in human CF cultured from multiple patients revealed a consistent pattern of expression with p38α being most abundant, followed by p38γ, then p38δ and only low expression of p38β (3% of p38α mRNA levels). Immunoblotting confirmed marked protein expression of p38α, γ and δ, with little or no expression of p38β. Phospho-ELISA and combined immunoprecipitation/immunoblotting techniques demonstrated that the proinflammatory cytokines IL-1α and TNFα selectively activated p38α and p38γ, but not p38δ. Selective p38α siRNA gene silencing reduced IL-1α-induced IL-6 and MMP-3 mRNA expression and protein secretion, without affecting IL-1α-induced IL-1β and MMP-9 mRNA expression. In conclusion, human CF express the α, γ and δ subtypes of p38 MAPK, and the α subtype is important for IL-1α-induced IL-6 and MMP-3 expression in this cell type.