Effects of Ovariectomy and 17β-Estradiol Replacement on the Activity of Dopamine D2 Receptors in the Selection of Macronutrients Carbohydrates, Lipids and Proteins in Females Rats

17β-estradiol modulates the activity of D2 receptors in the regulation of food intake and body weight. The functional lack of 17β-estradiol in postmenopausal women could create a dietary imbalance and cause body weight gain. This study aimed to better understand the interferences that could exist between 17β-estradiol, D2 receptors and the selection of carbohydrate, fat and protein consumption, as well as their consequences on body weight gain by using an animal model of the menopause. Ovariectomy exacerbates the consumption of foods rich in lipids. Thus confirming an inhibitory action of 17β-estradiol (E2) on the consumption of these types of foods. This consumption stimulates body weight gain, which is promoted by the high caloric content of these foods and not by the amount consumed. Our results showed a direct involvement of D2 receptors in food choice. This choice would be made according to the two (2) isoforms of the D2 receptors. The D2/BR isoform directs towards a high carbohydrate consumption, without causing a gain in body weight. While D2/SUL, promotes high fat food consumption, causing an increase in body weight. In women, 17β-estradiol modulates the activity ratio between these two D2 receptor isoforms to ensure energy and homeostatic balance, stabilizing food intake and body weight.

Neutrophil-derived interleukin-17A participates in neuroinflammation induced by traumatic brain injury

After brain injury, infiltration and abnormal activation of neutrophils damages brain tissue and worsens inflammation, but the mediators that connect activated neutrophils with neuroinflammation have not yet been fully clarified. To identify regulators of neutrophil-mediated neuroinflammation after traumatic brain injury, a mouse model of traumatic brain injury was established by controlled cortical impact. At 7 days post-injury(sub-acute phase), genome-wide transcriptomic data showed that interleukin 17 A-associated signaling pathways were markedly upregulated, suggesting that interleukin 17 A may be involved in neuroinflammation. Double immunofluorescence staining showed that interleukin 17 A was largely secreted by neutrophils rather than by glial cells and neurons. Furthermore, nuclear factor-kappaB and Stat3, both of which are important effectors in interleukin 17 A-mediated proinflammatory responses, were significantly activated. Collectively, our findings suggest that neutrophil-derived interleukin 17 A participates in neutrophil-mediated neuroinflammation during the subacute phase of traumatic brain injury. Therefore, interleukin 17 A may be a promising therapeutic target for traumatic brain injury.

Drug-induced entero-colitis due to interleukin-17 inhibitor use;capsule endoscopic findings and pathological characteristics:A case report

BACKGROUND Interleukin-17(IL-17)inhibitors are known to cause exacerbation or new onset of inflammatory bowel disease upon administration.However,few reports have described characteristic endoscopic and histopathologic findings,and no small intestinal lesions have been reported so far.CASE SUMMARY A woman in her 60s with psoriasis was administered ixekizumab(IXE),an anti-IL-17A antibody,for the treatment of psoriasis.Twenty months after commencing treatment,the patient visited our hospital because of persistent diarrhea.Blood tests performed at the time of the visit revealed severe inflammation,and colonoscopy revealed multiple round ulcers throughout the colon.A tissue biopsy of the ulcer revealed infiltration of inflammatory cells and granuloma-like findings in the submucosal layer.Capsule endoscopy revealed multiple jejunal erosions.After the withdrawal of IXE,the symptoms gradually improved,and ulcer reduction and scarring of the colon were endoscopically confirmed.CONCLUSION To the best of our knowledge,17 reports have documented IL-17 inhibitorinduced entero-colitis with endoscopic images,endoscopic findings,and pathological characteristics,including the present case.Nine of these cases showed diffuse loss of vascular pattern,coarse mucosa/ulcer formation in the left colon,and endoscopic findings similar to those of ulcerative colitis.In the remaining eight cases,discontinuous erosions and ulcerations from the terminal ileum to the rectum were seen,with endoscopic findings similar to those of Crohn’s disease.In this case,the findings were confirmed by capsule endoscopy,which has not been previously reported.

Effects of Ovariectomy and 17<i>β</i>-Estradiol Replacement on Dopamine D2 Receptors in Female Rats: Consequences on Sucrose, Alcohol, Water Intakes and Body Weight

Background: Mechanisms underlying overeating-induced obesity in post-menopausal woman include functional lack of 17β-estradiol dysregulating dopamine D2 receptors, thereby inducing food addiction, glucose craving or alcohol dependence through reward circuitry. This study aimed at further understanding 17β-estradiol and dopamine D2 receptors interferences in the etiology of woman obesity. Method: Seventy-two Wistar female rats weighing 200 - 205 g, individually-housed, were divided into non-ovariectomized control (C = 6 groups) and ovariectomized rats (OVX = 6 groups) which were concurrently subjected to the following treatments: Non-drug-treated (DMSO vehicle), 17β-estradiol (E2, 5 μg/kg, s.c.), sulpiride (SUL, 20 mg/kg, i.p.), bromocriptine (BR, 0.1 mg/kg, i.p.), E2 + SUL or E2 + BR, designating the 6 constitutive groups of either control or ovariectomy. Within each experimental group, consumption of different solutions (10% alcohol, 10% sucrose and water) as well as food intake and body weight were daily measured, for 10 consecutive days. Results: This study indicated that D2S was a specific inducer of alcohol and food intakes, but reduced sugar consumption. In addition, 17β- estradiol regulated the body weight set point, modulating D2S functions towards increased food intake at lower weights and decreased food intake at higher weights. D2S met the slow genomic actions induced by 17β-estradiol. Conversely, D2L inhibited alcohol and food intakes, but induced specifically sugar consumption, thereby regulating blood glucose levels and promoting energy expenditure in reducing body weight. Indeed, 17β-estradiol exerted a tonic inhibition on D2L which was released by OVX, exacerbating sugar intake and increasing body weight. D2L mediated the rapid metabolic effects of 17β-estradiol. Conclusion: Our results supported physiological data reporting that activation of the mostly expressed presynaptically D2S-class autoreceptors decreased dopamine release stimulating food intake, whereas activation of the predominantly postsynaptic isoform D2L receptors increased dopamine activity inhibiting food intake. Our studies indicated that 17β-estradiol acted on the two types of D2 receptors showing opposite functions to equilibrate energy intake vs. expenditure for weight set point regulation. Our data also supported biochemical findings reporting that 17β-estradiol induced D2 genes transcriptional regulation, thereby involving both types of D2 receptors in the etiology of obesity. The combined dysregulated effects of D2L and D2S receptors, as 17β-estradiol was lacking, would be causal factors underlying the etiology of obesity.

Effects of 17<i>β</i>-Estradiol on Dopamine D2 Receptors in Thiamine-Deficient Female Rats: Consequences on Sucrose, Alcohol, Water Intakes and Body Weight

Our previous studies showed that 17β-estradiol (E2) modulated dopamine D2 receptor in regulating body weight set-point. The aim of this study was to understand whether thiamine deficiency influenced the E2 modulation on dopamine D2 receptors, using bromocriptine mesylate (BR) and sulpiride (SUL) as selective central dopamine-D2 receptors agonist and antagonist respectively. We studied the E2-dopamine D2 receptors interferences in a 10-day thiamine-deficient female rats for which consumptions of water, sugar, alcohol and food were daily-recorded and their consequences on body weights assessed. Our results showed that the volume of water daily ingested doubled in thiamine-deficient female rats (OXT), while sugar and alcohol consumptions collapsed with decreased weight and food consumption. On the one hand, thiamine potentiated D2/BR activity (bromocriptine-activated D2 receptors) to induce sugar intake and inhibited the same D2/BR receptors to induce water intake. On the other hand, thiamine promoted D2/SUL receptors (sulpiride-inhibited D2 receptors) for enhanced alcohol intake, increased food consumption and weight gain. Taking together, thiamine modulated the actions of 17β-estradiol on both D2/BR and D2/SUL receptors activities.

Interleukin-17 levels in Helicobacter pylori-infected gastric mucosa and pathologic sequelae of colonization

AIM： To determine the role of interleukin （IL）-17 in gastric ulcerogenesis. METHODS： Thirty-six gastric ulcer （GU） patients and 29 non-ulcer （NU） patients were enrolled in this study. Mucosal biopsy samples were obtained from the gastric antrum and GU site during endoscopy. Samples were used in in situ stimulation for 48 h in the presence of 10 ug/mL phytohemagglutinin-P （PHA）, histological examination, and Helicobacter pylori（Hpylon） culture. IL-17 and IL-8 protein levels in culture supematants were assayed by ELISA. IL- 17 mRNA expression was analyzed by reverse transcriptasepolymerase chain reaction （RT-PCR）. Hpylori cagA and vacA status was assessed by reverse hybridization using a line probe assay （UPA）. IL-8 levels in culture supematants were assayed after AGS cells were co-cultured with Hpylori strain 26 695 or recombinant human （rh） IL-17. RESULTS： All 36 GU patients and 15 of 29 NU patients were found to be Hpy/or/-positive, while 14 NU patients were Hpylori-nogative. All 51 H pylori strains from both GU and NU patients were cagA- and vacAsl/ml-positive. Antral mucosal tissues from H pylori-positive patients contained significantly （H pylori-positive NU patients： median 467 pg/mg/protein, range 53-2 499; Hpylori negative NU patients： median 104 pg/mg/protein, range 16-312, P〈0.0005） higher levels of IL-17 than those from uninfected patients. IL-17 levels at the ulcer site were significantly （ulcer site： median 1 356 pcj/mg/protein, range 121-1 3730; antrum： median 761 pg/mg/protein, range 24-7 620, P〈0.005） higher than those at distant sites in the antrum. Biopsies from H pylori-positive GU and NU patients showed IL-17 mRNA expression in all samples whereas those from the antrum of the Hpylori-negativecontrols showed no detectable expression. A significant correlation was seen between IL-17 and IL-8 levels at each biopsy site （ulcer： r = 0.62,P〈0.0001; antrum： r = 0.61, P〈0.0001） in GU patients. RhIL-17 and Hpylori strain 26 695 each stimulated IL-8 production from AGS cells. CONCLUSION： IL-17 may play an important role in the inflammatory response to Hpyloricolonization, and may ultimately influence the outcome of H pylori-associated diseases that arise within the context of gastritis.

Identification and functional characterization of fish IL‑17 receptors suggest important roles in the response to nodavirus infection

Th17 is a lymphocyte T helper(Th)subpopulation relevant in the control and regulation of the immune response characterized by the production of interleukin(IL)-17.This crucial cytokine family acts through their binding to the IL-17 receptors(IL-17R),having up to six members.Although the biology of fish Th17 is well-recognized,the molecular and functional characterization of IL-17 and IL-17R has been limited.Thus,our aim was to identify and characterize the IL-17R repertory and regulation in the two main Mediterranean cultured fish species,the gilthead seabream(Sparus aurata)and the European sea bass(Dicentrarchus labrax).Our in silico results showed the clear identification of six members in each fish species,from IL-17RA to IL-17RE-like,with well-conserved gene structure and protein domains with their human orthologues.All of them showed wide and constitutive transcription in naïve tissues but with highest levels in mucosal tissues,namely skin,gill or intestine.In leucocytes,T mitogens showed the strongest up-regulation in most of the il17 receptors though il17ra resulted in inhibition by most stimulants.Interestingly,in vivo nodavirus infection resulted in alterations on the transcription of il17 receptors.While nodavirus infection led to some increments in the il17ra,il17rb,il17rc and il17rd transcripts in the susceptible European sea bass,many down-regulations were observed in the resistant gilthead seabream.Our data identify the presence and conservation of six coding IL-17R in gilthead seabream and European sea bass as well as their differential regulation in vitro and upon nodavirus infection.

Vitamin D deficiency: Correlation to interleukin-17, interleukin-23 and PⅢNP in hepatitis C virus genotype 4

AIM: To assess vitamin D (Vit D) abnormalities in hepatitis C infected patients and their relationship with interleukin (IL)-17, IL-23 and N-terminal propeptide of type Ⅲ pro-collagen (PⅢNP) as immune response mediators. METHODS: The study was conducted on 50 Egyptian patients (36 male, 14 female) with hepatitis C virus (HCV) infection, who visited the Hepatology Outpatient Clinic in the Endemic Disease Hospital at Cairo University. Patients were compared with 25 ageand sexmatched healthy individuals. Inclusion criteria were based on a history of liver disease with HCV genotype 4 (HCV-4) infection (as new patients or under followup). Based on ultrasonography, patients were classified into four subgroups; 14 with bright hepatomegaly; 11 with perihepatic fibrosis; 11 with hepatic cirrhosis; and 14 with cirrhosis and hepatocellular carcinoma (HCC).Total Vit D (i.e., 25-OH-Vit D) and active Vit D [i.e., 1,25-(OH) 2 -Vit D] assays were carried out using commercial kits. IL-17, IL-23 and PⅢNP levels were assayed using enzyme linked immunosorbent assay kits, while HCV virus was measured by quantitative and qualitative polymerase chain reaction. RESULTS: Levels of Vit D and its active form were significantly lower in advanced liver disease (hepatic cirrhosis and/or carcinoma) patients, compared to those with bright hepatomegaly and perihepatic fibrosis. IL-17, IL-23 and PⅢNP levels were markedly increased in HCV patients and correlated with the progression of hepatic damage. The decrease in Vit D and active Vit D was concomitant with an increase in viral load, as well as levels of IL-17, IL-23 and PⅢNP among all subgroups of HCV-infected patients, compared to normal healthy controls. A significant negative correlation was evident between active Vit D and each of IL-17, IL-23 and PⅢNP (r = -0.679, -0.801 and -0.920 at P < 0.001, respectively). HCV-infected men and women showed no differences with respect to Vit D levels. The viral load was negatively correlated with Vit D and active Vit D (r = -0.084 and -0.846 at P < 0.001, respectively), and positively correlated with IL-17, IL-23 and PⅢNP (r = 0.951, 0.922 and 0.94 at P < 0.001, respectively). Whether the deficiency in Vit D was related to HCVinduced chronic liver disease or was a predisposing factor for a higher viral load remains to be elucidated. CONCLUSION: The negative correlations between Vit D and IL-17, IL-23 and PⅢNP highlight their involvement in the immune response in patients with HCV-4related liver diseases in Egypt.

Interleukin-17 plays a critical role in the acute rejection of intestinal transplantation

AIM:To investigate the role of interleukin(IL)-17 in small bowel allograft rejection.METHODS:We detected the expression of helper T cell 17(Th17)cells in biopsy specimens from 3 cases of living small bowel transplantation in our department through immunofluorescence stain.We then established a rat heterotopic small bowel transplantation model.The rats were sacrificed on the 1st,2nd,3rd,5th, and 7th d after small bowel transplantation.The degrees of transplantation rejection in rat intestine graft were examined through hematoxylin eosin(HE)stain, and the expression of Th17 cells in rat intestine graft were detected through immunofluorescence stain. In addition,the recipient rats undergoing intestinal transplantation were administrated with mouse-anti-rat IL-17 monoclonal antibody(mAb),and the survival of rats was analyzed.The recipient rats which received mouse-anti-rat IL-17 mAb treatment were sacrificed on the 1st,2nd,3rd,5th,and 7th d after small bowel transplantation.The degrees of transplantation rejection and the expression of Th17 cells in rat intestine graft were detected through HE and immunofluorescence stain. The expression of IL-17,IL-1β,tumor necroses factor receptor-α(TNF-α),IL-6,and IL-8 in the intestine graft or serum were also detected. RESULTS:The expressions of Th17 cells ran parallel with the degree of acute rejection in human intestine grafts.The intestine graft rejection of rats was aggravated with prolonged duration after intestinal transplantation,and the expressions of Th17 cells were also correlated with the degree of acute rejection in rat intestine grafts.Administration of mouse-anti-rat IL-17 mAb prolonged the survival of rats after small bowel transplantation(P<0.001).Furthermore,we found that the administration of mouse-anti-rat IL-17 mAb significantly decreased the intensity of CD4+IL-17+Th17 cells in intestine grafts on the 2nd,3rd,5th,and the 7th d (97.22±4.05vs 12.45±2.02 on the 7th d,P<0.0001), and suppressed the severity of acute rejection.The expression of IL-17 in the intestine graft declined after mouse-anti-rat IL-17 mAb administration on the 2nd,3rd,5th,and the 7th d(0.88±0.03 vs 0.35±0.02 on the 7th d,P<0.0001).We also detected the IL-17 serum level and found that the IL-17 level reduced from the 1st d to the 7th d(6.52±0.18 ng/mL vs 2.04±0.15 ng/mL on the 7th d,P<0.0001).No significant difference in the level of IL-17 mRNA in the intestine graft was identified between the two groups.The levels of IL-1β,TNF-α, IL-6,and IL-8 mRNA in the intestine graft after the administration of mouse-anti-rat IL-17 mAb were also tested.We found that on the 3rd,5th,and 7th d after intestinal transplantation,administration of mouse-anti- rat IL-17 mAb significantly inhibited the levels of IL-1β (12.11±1.16 vs 1.27±0.15 on the 7th d,P<0.001), TNF-α(27.37±2.60 vs 1.06±0.26 on the 7th d,P< 0.001),IL-6(21.43±1.79 vs 1.90±0.32 on the 7th d, P<0.001),and IL-8(20.44±1.44 vs 1.34±0.20 on the 7th d,P<0.001)mRNA in the intestine graft. CONCLUSION:IL-17 may act as a promising and potent target for inhibiting acute rejection after small bowel transplantation.

Interleukin-17 SNPs and serum levels increase ulcerative colitis risk: A metaanalysis

AIM: To investigate the associations of interleukin-17 (IL-17) genetic polymorphisms and serum levels with ulcerative colitis (UC) risk.

Polymorphism in the interleukin-17A promoter contributes to gastric cancer

AIM:To evaluate the contribution of the G-197A polymorphism in the interleukin-17(IL-17)promoter region to gastric cancer risk in an Iranian population.METHODS:We performed a case control study using samples from 161 individuals with gastric cancer and171 healthy controls.For each individual,the G-197A genotype was determined by restriction fragment length polymorphism analysis of polymerase chain reaction-amplified fragments.Statistical analyses were performed to determine whether any demographic or behavioral factors,infection with Helicobacter pylori(H.pylori),or a particular G-197A genotype was associated with gastric cancer risk.RESULTS:We found that the G-197A genotype wassignificantly associated with increased gastric cancer risk(P=0.001).Patients who were homozygous(AA)at position-197 were 2.9 times more likely to develop disease(95%CI:1.56-5.4;P=0.001).Furthermore,logistic regression analysis revealed that the presence of a single A allele increased the risk of gastric cancer up to 1.7-fold(95%CI:1.26-2.369;P=0.001).This association was observed for early stage gastric adenocarcinomas only,and was not linked to H.pylori infection.CONCLUSION:These results suggest that carrying one or more G-197A polymorphisms at position-197 in the IL-17 promoter region significantly increases gastric cancer risk in this patient population.

Expression of Interleukin-17 in Lung and Peripheral Blood of Asthmatic Rats and the Influence of Dexamethasone

The expression of interleukin-17 （IL-17） in lung and peripheral blood of asthmatic rats and the influence of dexamethasone, and the role of IL-17 in the pathogenesis of asthma were investigated. Thirty Sprague-Dawley （SD） adult rats were randomly divided into three groups （n=10 in each group）： normal group, asthmatic group, and dexamethasone-interfered group. Rat asthmatic model was established by intraperitoneal （i.p.） injection of 10% ovalbumin （OVA） and challenge with 1% OVA via inhalation. Rats in dexamethasone-interfered group were pretreated with dexamethasone （2 mg/kg, i.p.） 30 min before each challenge. The expression of IL-17 protein in serum and bronchoalveolar lavage fluid （BALF） was detected by ELISA. The expression of IL-17 mRNA in peripheral blood mononuclear cells （PBMC） and BALF cells was semi-quantitatively detected by RT-PCR. The expression of IL-17 protein in serum and BALF of asthmatic rats was significantly elevated as compared with normal rats and dexamethsone-interfered rats （P〈0.01）, and there was significant difference between normal rats and dexamethsone-interfered rats （P〈0.05）. The expression of IL-17 mRNA in PBMC and BALF cells of asthmatic rats was markedly increased as compared with normal rats and dexamethsone-interfered rats （P〈0.01）, and significant difference was found between normal rats and dexamethsone-interfered rats （P〈0.05）. It was concluded that the expression of IL-17 was increased significantly in asthmatic rats and could be inhibited partly by dexamethasone, suggesting that IL-17 might play an important role in the pathogenesis of asthma as an inflammation regulation factor.

The Expression of Interleukin-17, Interferon-gamma, and Macrophage Inflammatory Protein-3 Alpha mRNA in Patients with Psoriasis Vulgaris

Summary: To investigate the role of Interleukin-17 (IL-17), Interferon-gamma (IFN-γ), and macrophage inflammatory protein-3 alpha (MIP-3α) in the pathogenesis of psoriasis, reverse transcriptase-polymerase chain reaction (RT-PCR) was used to semi-quantitatively analyze the mRNA expression of IL-17, IFN-γ, and MIP-3α in 31 psoriatic lesions and 16 normal skin tissues. The results showed that the mRNA of the three cytokines was present in all specimens. And the expression level of IL-17 mRNA in skin lesions was 1.1416±0.0591, which was significantly higher than that in normal controls (0.8788±0.0344, P<0.001). The expression levels of IFN-γ mRNA were 1.1142±0.0561 and 0.9050±0.0263, respectively, with significant difference(P<0.001). And the expression levels of MIP-3α mRNA in psoriatic lesions was 1.1397±0.0521, which was markedly higher than that in normal controls (0.8681±0.0308, P<0.001). These findings indicate that up-regulated expression of IL-17, IFN-γ, and MIP-3α might be involved in the pathogenesis of psoriasis.

Unexpected alliance between syndecan-1 and innatelike T cells to protect host from autoimmune effects of interleukin-17

Innate-like T cells, namely natural killer T(NKT) and γδ T cells, play critical roles in linking innate and adaptive immune responses through rapid production of cytokines. Prominent among these cytokines is interleukin-17(IL-17), which is a potent proinflammatory cytokine that plays a critical role in host defense against fungi and extracellular bacteria. However, excessive IL-17-production promotes autoimmune diseases, including psoriasis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematosus. IL-17 has also been implicated in regulating body fat, which is highly relevant given rises in obesity and type 2 diabetes. NKT cells, γδ T cells and mucosal-associated invariant T cells(MAIT) are the major sources of IL-17 involved in protection of mucosal surfaces from opportunistic infections and causing autoimmunity when become dysregulated. Given the pathogenic effects of IL-17, efforts have been directed towards understanding mechanisms that guard against IL-17 overproduction. One novel potent mechanism is mediated by the heparan sulfate proteoglycan, syndecan-1(sdc1), which is selectively expressed by IL-17-producing subsets of NKT and γδ T cells. This unexpected role for sdc1 is uncovered by analysis of NKT and γδ T cells in sdc1-deficient mice. In this mini-review, we discuss selective expression of sdc1 by these innate T cells and consequences of its absence on IL-17 homeostasis and pathological implications.

Suppressive effect of pectic polysaccharides extracted from Rauwolfia verticillata(Lour.) Baill.var.hainanensis Tsiang on inflammation by regulation of NF-κB pathway and interleukin-17 in mice with dextran sulphatesodium-induced ulcerative colitis

Objective:To investigate the effects of pectic polysaccharides extracted from Rauwolfia verticillata(Lour.) Baill.var.hainanensis Tsiang on an experimental murine colitis model.Methods:Experimental colitis was induced by dextran sulfate sodium(DSS),and mice were divided into 4 groups:control.DSS alone.DSS plus SASP,DSS plus pectic polysaccharides.The disease activity index(DAI) and histological score were observed.The tumor necrosis factor(TNF)-α and interleukin(IL)-17 levels were measured by enzyme-linked immunosorbent assay.I κ B and NF-κB p65 expression were assessed by western blot analysis.Myeloperoxidase(MPO) activity was determined by using MPO assay kit.Re.sults:Administration of pectic polysaccharides significantly reduced the severity of DSS-induced colitis as assessed by DAT and histological score,and resulted in down regulation of MPO activity and NF-κB p65 expression and subsequent degradation of IκB protein,strikingly reduced the production of TNF-α and IL-17.Conclusions:Pectic polysaccharides extracted from Rauvolfia verticillata(Lour.)Baill.var.hainanensis Tsiang exerts beneficial effects in experimental colitis and may therefore provide a useful therapeutic approach for the treatment of UC.

Regulation of the mesenchymal stem cell fate by interleukin-17: Implications in osteogenic differentiation

Bone regeneration is a tightly regulated process that ensures proper repair and functionality after injury.The delicate balance between bone formation and resorption is governed by cytokines and signaling molecules released during the inflammatory response.Interleukin(IL)-17A,produced in the early phase of inflammation,influences the fate of osteoprogenitors.Due to their inherent capacity to differentiate into osteoblasts,mesenchymal stem/stromal cells(MSCs)contribute to bone healing and regeneration.This review presents an overview of IL-17A signaling and the leading cellular and molecular mechanisms by which it regulates the osteogenic differentiation of MSCs.The main findings demonstrating IL-17A’s influence on osteoblastogenesis are described.To this end,divergent information exists about the capacity of IL-17A to regulate MSCs’osteogenic fate,depending on the tissue context and target cell type,along with contradictory findings in the same cell types.Therefore,we summarize the data showing both the pro-osteogenic and anti-osteogenic roles of IL-17,which may help in the understanding of IL-17A function in bone repair and regeneration.

Interleukin-17A gene variants and risk of coronary artery disease:a large angiography-based study

Background Recent studies have also revealed that interleukin(IL)-17A plays a key role in atherosclerosis and its complication,but the relationship of its common variants with coronary artery disease(CAD) has not been extensively studied.Methods We systematically screened sequence variations in the IL17A gene and designed an angiog-raphy -based case-controlled study consisting of 1031 CAD patients and 935 control subjects to investigate the association between the selected polymorphisms of IL-17A gene and CAD risk in Chinese Han population.Results Frequencies of IL17A rs8193037 GG homozygote and G allele were significantly higher in the patient group than those in the control group(P【0.001;OR=0.68;95%CI=0.54-0.85).Stratification analysis showed that the IL17A rs8193037 G allele significantly increased the risk of CAD only among male subjects (P=0.001;OR=0.63;95%CI=0.47-0.83).After adjustment for conventional risk factors,binary logistic regression analysis showed that the G allele carriers(GG +AG) had significantly increased CAD risk compared with the AA homozygotes (adjusted P【0.001;OR 0.43;95%CI,0.33- 0.58).ELISA showed augmented IL17A production in plasma of the AMI patients.Conclusions Based on our data,we speculated that the SNP rs8193037 of IL17A gene is significantly associated with CAD risk in Chinese Han population and the rs8193037 G allele which is associated with increased expression of IL17A in AMI patients may be an independent predictive factor for CAD.

Interleukin-17 mediates liver progenitor cell transformation into cancer stem cells through downregulation of miR-122

Objective:Cancer stem cells(CSCs)have been the focus of several studies because oftheir involvement in cancer initiation and progression.CSCs were identified in 28%to 50%of hepatocellular carcinomas(HCCs).The origin of CSCs is still unclear,but it has been recently suggested that CSCs could originate from the transformation of liver progenitor cells(LPCs)during chronic liver inflammation.

Role of liver X receptors alpha agonist on expressions of LPS-induced inflammatory response associated factor IRAK-4 and NF-kappaB in Kupffer cells

Objective： To explore the role of activated liver X receptor α （LXRα） on the expressions of interleukin-1 receptor associated kinase-4 （IRAK-4） and NF-kappaB （NF-κB） in the inflammatory response which induced by LPS in the Kupffer cells and to investigate the possible mechanisms of LXRα negative regulation of inflammatory response. Methods： The Kupffer cells were isolated from male Kunming mice by collagen perfusion in situ. And these cells were divided into 4 groups： normal control group, LPS treatment group, LXRct agonist T0901317 treatment group, LPS and T0901317 combined treatment group. The LPS treatment group were treated with a final concentration of 1 μg/ml LPS in RPMI 1640 and cultured for 6 h, the T0901317 treatment group were treated with a final concentration of 5 μg/ml in RPMI 1640 and cultured for 24 h, and the combined treatment group received pre-culture for 24 h with a final concentration of 1μg/ml T0901317 in RPMI 1640 and then cultured for 6 h with a final concentration of 5 μg/ml LPS in RPMI 1640. All groups were cultured for 30 h. The expression of LXRα, IRAK-4 and NF-κB at mRNA and protein levels were detected by real-time PCR and Western blotting, and the TNF-α and IL-1β levels were detected by ELISA. Results： The levels of LXRα mRNA and protein were highest in T0901317 group, and lowest in LPS group （P〈0.05）. The level of IRAK4 and NF-κB mRNAs and proteins were evidently lower in the Combined-treated group than in LPS group （P〈0.05）. And the level of TNF-α and IL-1 were observed highest in LPS group （P〈0.05）, but no difference among the Control group, T0901317 group and Combined-treated group （P〉0.05）. Conclusion： These date suggest that the LXR agonists can effectively up-regulate the expressions of LXRα mRNA and protein and inhibit the inflammatory response. This may be via down-regulating the expressions of IRAK4 and NF-κB at mRNA and protein levels.

Syndecan-1-coating of interleukin-17-producing natural killer T cells provides a specific method for their visualization and analysis

Natural killer T cells(NKT cells) are innate-like T cells that acquire effector functions while developing in the thymus, polarize into three distinct functional subsets viz. NKT1, NKT2 and NKT17 cells that produce interferon(IFN)-γ, interleukin(IL)-4 and IL-17, respectively. However, there has been no unique surface markers that define each subsets, forcing investigators to use intracellular staining of transcription factors and cytokines in combination of surface markers to distinguish among these subsets. Intracellular staining, however, causes apoptosis and prevents subsequent utilization of NKT cells in functional in vitro and in vivo assays that require viable cells. This limitation has significantly impeded understanding the specific properties of each subset and their interactions with each other. Therefore, there has been fervent efforts to find a specific markers for each NKT cell subset. We have recently identified that syndecan-1(SDC-1; CD138) as a specific surface marker of NKT17 cells. This discovery now allows visualization of NKT17 in situ and study of their peripheral tissue distribution, characteristics of their TCR and viable sorting for in vitro and in vivo analysis. In addition, it lays the ground working for investigating significance of SDC-1 expression on this particular subset in regulating their roles in host defense and glucose metabolism.