Ozone is a common environmental air pollutant leading to respiratory illness. The mechanisms regulating ozone-induced airway inflammation remain poorly understood. We hypothesize that ozone-triggered inflammasome activation and interleukin (IL)-1 production regulate neutrophilic airway inflammation through IL-17A. Pulmonary neutrophilic inflammation was induced by extended (72 h) low-dose (0.7 ppm) exposure to ozone. IL-1 receptor 1 (Il1r1)(-/-), Il17a(-/-) mice and the caspase-1 inhibitor acetyl-YVAD-chloromethylketone (Ac-YVAD-cmk) were used for in vivo studies. Cellular inflammation and protein levels in bronchial alveolar lavage fluid (BALF), cytokines, and IL-17A-producing γδT-cells, as well as mitochondrial reactive oxygen species (ROS), mitochondrial DNA (mtDNA) release, and inflammasome activation in lung macrophages were analyzed. Ozone-induced neutrophilic airway inflammation, accompanied an increased production of IL-1β, IL-18, IL-17A, Granulocyte-colony stimulating factor (G-CSF), Interferon-γ inducible protein 10 (IP-10) and BALF protein in the lung. Ozone-induced IL-17A production was predominantly in γδT-cells, and Il17a-knockout mice exhibited reduced airway inflammation. Lung macrophages from ozone-exposed mice exhibited higher levels of mitochondrial ROS, enhanced cytosolic mtDNA, increased caspase-1 activation, and higher production of IL-1β. Il1r1-knockout mice or treatment with Ac-YVAD-cmk decreased the IL-17A production and subsequent airway inflammation. Taken together, we demonstrate that ozone-induced IL-17A and neutrophilic airway inflammation is orchestrated by the caspase-1-IL-1 cascade.

We evaluated the 2G-NN16-carbosilane dendrimer activities in Th17 response as a potential therapy for Th17 deregulated pathologies. IL17A, IL17F, IL22, IL23 and other interleukins secreted by Th17 cells CD4+ cells were down regulated when cells were cultured in the presence of this dendrimer. Furthermore, IL17F and IL17A protein levels in splenocytes from mice pretreated with 2G-NN16 dendrimer in a Th17 induction mouse model were lower than those corresponding to PBS treated mice. Treatment of mice with 2G-NN16 inhibited the Th17 response causing much more pathogenicity as indicated by the increase in the number of Candida albicans colonies in the kidneys as compared to PBS-treated mice. All these results suggest a potential pharmacological application for this dendrimer in the therapy of Th17-mediated diseases.

OBJECTIVE

The aim of this study was to correlate IL-6, IL-17A, IFNγ, and IL-22 production with asthma disease severity and to evaluate if methylprednisolone downregulated cytokine production in peripheral blood mononuclear cells (PBMCs).

METHODS

Forty-two children with chronic persistent asthma and 34 non-asthmatic children were selected. Cytokines were quantified by ELISA from serum or PBMCs supernatants, after the PMA and Ionomycin stimulation, with or without methylprednisolone at 100 µM.

RESULTS

Our data showed undetectable levels of serum cytokines in most patients and controls. In the PBMCs, we have observed a higher production of IL-17A than IL-22 among asthmatics and controls, although it is not statistically significant. IL-6, IFNγ, and IL-17A levels were significantly reduced after methylprednisolone treatment (p = 0.02, 0.03, and 0.03, respectively) in Severe Persistent Asthma (SPA) and in Moderate Persistent Asthma (MPA), (p = 0.007, 0.01, and 0.007, respectively). However, IL-22 levels were unaffected (SPA, p = 0.12 and MPA, p = 0.93).

CONCLUSIONS

Methylprednisolone downregulated IL-6, IL17A, and IFNγ, but not IL-22, in stimulated PBMCs from asthmatic children indicating that methylprednisolone has no effect on IL-22 production by PBMCs.

Inflammatory cytokines have been established to be involved in the pathogenesis of rheumatoid arthritis (RA). The genetic polymorphisms in the interleukin (IL) 23 receptor (IL23R), IL21, and IL17 have been associated with RA risk. However, there is no conclusive understanding of the genes encoding the immunoinflammatory IL-21-IL-23R-IL-17A pathway in RA aetiopathogenesis. This meta-analysis was conducted to attain this goal. A comprehensive literature search was conducted in Scopus and PubMed to look for the relevant case-control studies up until 2018. A Bayesian hierarchical meta-analysis was carried out to assess the association between the polymorphisms and the risk of RA. The association was estimated by calculating the logarithm of odds ratio (Log OR) and 95% credible interval (95% CI). In this meta-analysis, 37 case-control studies comprising 23,506 RA patients and 25,984 healthy individuals were found for analyzing the IL23R, IL21, and IL1A gene polymorphism and risk of RA. In the IL23R gene rs1343151 SNP, the minor A allele significantly increased the risk of RA (Log OR = 0.085, 95% CI = 0.008, 0.156). Moreover, the minor AA genotype was significantly associated with increased RA risk (Log OR = 0.176, 95% CI = 0.028, 0.321). In addition, the C allele of the IL23R gene rs2201841 SNP significantly decreased the disease risk (Log OR = -0.544, 95% CI = -1.0, -0.065). Since Bayesian meta-analysis is a powerful strategy to pool the data, it can be mentioned that genetic polymorphisms of IL23R, but not IL21 and IL17A, are involved in susceptibility to RA.

The prognosis of autoimmune thyroid disease (AITD) including Graves' disease (GD) and Hashimoto's disease (HD) is difficult to predict. We previously suggested that Th17 cells may be associated with the pathogenesis of AITD. However, the association between gene polymorphisms in Th17-related genes and the prognosis of AITD was not clarified. To clarify this association, we genotyped 12 polymorphisms in 11 Th17-related genes (IL1Ra, IL6R, IL17R, IL21R, IL23R, CCR6, SOCS3, RORC, IL17A, IL17F and IL21) in 142 HD patients including 58 patients with severe HD and 48 patients with mild HD, 170 patients with GD including 81 patients with intractable GD and 49 patients with GD in remission, and 84 healthy volunteers. The frequency of the IL17F rs763780 T allele was higher in patients with severe HD than in patients with mild HD (p = .008). The frequency of the IL17R rs9606615 T allele was higher in patients with HD than in normal subjects (p = .011). The frequencies of the SOCS3 rs4969170 AA genotype, CCR6 rs3093024 AA genotype, and IL21 rs907715 AA genotype were higher in patients with intractable GD than in patients with GD in remission (p = .035, p = .002 and p = .030, respectively). In conclusion, IL17R rs9607715 and IL17F rs763780 polymorphisms are associated with the susceptibility and severity of HD, respectively. IL21 rs907715, SOCS3 rs4969170 and CCR6 rs3093024 polymorphisms are associated with the intractability of GD.

Designing strategies for targeting antigens to dendritic cells is a major goal in vaccinology. Here, PLGA (poly lactic-co-glycolic acid) microspheres and with several surface modifications that affect to their uptake by human blood primary dendritic cells and monocytes have been evaluated. Higher uptake was found by all the cell types when cationic microspheres (PLGA modified with polyethylene imine) were used. These cationic particles were in vivo evaluated in mice. In addition, MPLA(1) or poly(I:C)(2) and α-GalCer(3) were also encapsulated to address their adjuvant effect. All the microspheres were able to produce humoral immune responses, albeit they were higher for cationic microspheres. Moreover, surface charge seemed to have a role on biasing the immune response; cationic microspheres induced higher IFN-γ levels, indicative of Th1 activation, while unmodified ones mainly triggered IL4 and IL17A release, showing Th2 activation. Thus, we have shown here the potential and versatility of these MS, which may be tailored to needs.

BACKGROUND

Asthma and rhinitis have a complex etiology, depending on multiple genetic and environmental risk factors. An increasing number of susceptibility genes are currently being identified, but the majority of reported associations have not been consistently replicated across populations of different genetic backgrounds.

OBJECTIVE

To evaluate whether polymorphisms of IL4R (rs1805015), IL13 (rs20541), IL17A (rs2275913) and GSTP1 (rs1695) genes are associated with rhinitis and/or asthma in adults of Portuguese ancestry.

METHODS

192 unrelated healthy individuals and 232 patients, 83 with rhinitis and 149 with asthma, were studied. All polymorphisms were detected by real time polymerase chain reaction (PCR) using TaqMan assays.

RESULTS

Comparing to controls, significant association with asthma was observed for GSTP1 rs1695 AA genotype (odds ratio (OR) - 1.96; 95% CI - 1.18 to 3.25; p=0.010). The association sustains for allergic asthma (OR - 2.17; 95% CI - 1.23 to 3.80; p=0.007). IL13 rs20541 GG genotype was associated with less susceptibility to asthma (OR - 0.55, 95% CI - 0.33 to 0.94, p=0.028). Among patients, IL17A rs2275913 AA genotype was less associated with asthma than with rhinitis (OR - 0.20; 95% CI of 0.07 to 0.56; p=0.002). A similar association was found for IL13 rs20541 GG genotype (OR - 0.48; 95% CI of 0.25 to 0.93; p=0.031). There were no significant differences in the distribution of allelic and genotypic frequencies between patients and controls for the IL4R polymorphism' analyzed.

CONCLUSIONS

These results support the existence of a significant association between GSTP1 rs1695 and IL13 rs20541 SNPs, with susceptibility to asthma, in the population studied. Different genotype profiles of IL17A and IL13 genes seem to influence the clinical pattern of disease expression mainly confined to the upper airways, as rhinitis, or including the lower airways, as asthma.

Oral lichen planus (OLP) is a complex immunological disorder, mediated in part by the release of cytokines from activated T-cells. Of late, two closely related T-helper (Th) cell subsets; regulatory T-cells (Tregs; FoxP3(+)) and Th17 cells (IL17(+)) have been described in various chronic inflammatory diseases. The aim of this study was to determine the expression of FoxP3 and IL17 in OLP using immunohistochemistry (IHC) and quantitative real-time reverse transcriptase polymerase chain reaction (qPCR). For IHC, formalin fixed, paraffin embedded archival specimens, an OLP group (n=10) and a non-specific inflammatory (NSI) control group (n=9) were used. In addition, 12 fresh tissue samples were used to determine gene expression of FoxP3 and IL17. Significantly more FoxP3(+) cells were present in OLP than in NSI. IL17(+) cells were significantly more frequent in the control tissues than in OLP. The gene expression experiments revealed a significantly higher expression of FoxP3 in OLP when compared to the controls. IL17 gene expression was not different between the groups. Double labelling immunofluorescence indicated co-localisation of IL17 with tryptase(+) mast cells. These findings suggest FoxP3(+) Tregs have a more prominent role in the pathogenesis of OLP when compared to IL17(+)cells.

BACKGROUND

CpG island aberrant methylation is shown to be an important mechanism in gene silencing. The important role of IL-17 in inflammatory response to H. pylori colonization has been indicated. We investigated the influence of IL17A polymorphisms, -197 G>> A (rs2275913) and *1249 C>> T (rs3748067), on the methylation of DAPK and CDH1.

METHODS

Gastric mucosal samples were obtained from 401 subjects without malignancies. Methylation status of gene was determined by MSP. The genotyping of IL17A was performed by PCR-SSCP.

RESULTS

Methylations of DAPK and CDH1 were seen in 196 and 149 of all 401 subjects, respectively. Overall, *1249 T carrier was associated with a decreased risk for DAPK methylation, whereas -197 G>> A was not. In the subjects older than 60 years old, *1249 T carrier was more strongly associated with gene methylation and -197 A carrier tended to be associated with an increased risk for CDH1 methylation. When evaluating by inflammation promoting haplotype (-197 mutant carrier with *1249 homozygote), this haplotype had a more strongly increased risk for both DAPK and CDH1 methylations in comparatively older subjects. Both atrophy and metaplasia scores were significantly increased with age in -197 A carrier or *1249 CC homozygote, whereas were not in -197 GG homozygote or *1249 T carrier. PG I/II ratio was more significantly decreased in -197 A carrier than in GG homozygote under influence of H. pylori infection.

CONCLUSIONS

In -197 A allele carrier with *1249 CC homozygote, the methylations of both DAPK and CDH1 may be increased gradually, but more rapidly than the other genotypes, with age and altered gastric mucosal structure induced by H. pylori infection.

In previous work, we found significant associations of horse polymorphic microsatellite and immunity-related (IR) gene markers with Rhodococcus equi infection of foals. Here, a statistically significant association between a single nucleotide polymorphism (SNP) within the interleukin 7 receptor-encoding gene (IL7R) with high R. equi burden in transtracheal aspirates was found (Fisher's F = 0.043, odds ratio: 8.00, 95% confidence interval: 1.127-56.795). Further positional and/or functional candidate genes investigated TLR2, IL13, IL17A, IL28R, TACE/ADAM 17 and GBP1, were not associated with infection in this study. SNPs analysed were found by sequencing and appropriate restriction fragment length polymorphism markers were developed. Their associations with R. equi infection were tested by genotyping thoroughbred foals from the original study. The association was confirmed by analysing genotypes composed with genes previously reported to be associated with R. equi infection in the same group.

Antioxidant lipoic acid (LA) has been reported to have a potential prophylactic effect on bone loss induced by high-fat diet (HFD). The aim of this work was to examine the hypothesis that LA decreases bone resorption-related gene expression and increases bone formation-related gene expression in HFD-fed mice, preventing a shift in the bone metabolism balance toward resorption. Male C57BL/6 mice were fed a normal diet, HFD, or HFD plus 0.1% LA for 12 weeks. The bone metabolism-related genes differentially expressed between mice fed HFD and those fed HFD supplemented with LA were identified through complementary DNA microarray. The supplemental LA significantly increased bone mineral density and bone antioxidant capacity in mice fed HFD (P < .05). Compared with the HFD-fed mice, LA induced the decreased expression of genes associated with bone resorption, such as Mmp9 (1.9-fold) and Ctsk (2.3-fold), and increased those genes associated with bone formation, such as Col1a1 (1.3-fold) and Alp1 (1.5-fold). Furthermore, LA upregulated many genes involved in the Igf signaling pathway, such as Igf-1 (increased 1.7-fold), and downregulated genes involved in the p53 apoptotic pathway, such as p53 (decreased 2.3-fold), thus attenuating the HFD-induced inhibition of bone formation. Lipoic acid induced upregulation of Il12a (2.1-fold) and downregulation of Tgfbr1 (4.3-fold) and Il17a (11.3-fold), which may reduce bone resorption. In summary, LA supplementation during HFD could affect bone density, altering gene expression.

IL-6 and IL-23 are both pleiotropic cytokines involved in the regulation of the immune response, inflammation, and hematopoeisis. They also could mediate effector cells and tolerance mediated by cells with regulatory function. Inflammatory bowel disease (IBD) is associated with a reduced ratio of Treg cells ato Th17 effector cells in peripheral blood and is characterised by a pro-inflammatory cytokine microenvironment which supports the continued generation of Th17 cells. It is well described in adults but little is known in a pediatric population. This study was aimed to investigate the role of IL-6, IL-23 and its association with Treg and Th17 subsets in pediatric IBD patients. Peripheral blood mononuclear cells from patients and controls were stimulated with PMA, ionomycin, and brefeldin A. The frequencies of CD4+Foxp3+ cells, and CD4+IL17a+ cells were analyzed by flow cytometry. The serum level of IL-6 and IL-23 was determined by Elisa kit. The mRNA expression of Foxp3, IL-17a, IL-6 and IL-23 was detected by real-time quantitative PCR. The ratio of Treg/Th17 decreased in pediatric IBD patients, and it strongly correlated with IL-6 and IL-23. The present study provides a quantitative analysis regarding the Th17/Treg cell balance in peripheral blood of children with IBD and its association with serum IL-6 and IL-23 level.

BACKGROUND

Dietary fiber intake leading to short-chain fatty acid (SCFA) production could be a strategy to combat intermittent bouts of inflammation during ulcerative colitis.

OBJECTIVE

Our objective was to evaluate dietary potato fiber (PF) in attenuating inflammation using a dextran sodium sulfate (DSS)-induced colitis mouse model. We hypothesized that PF would show anti-inflammatory effects compared with cellulose due in part to SCFA production.

METHODS

Male C57Bl/6J mice were fed diets containing either 8% cellulose or 14.5% PF for a 22-d feeding study. Starting on study day 14, mice were provided either distilled water (control) or 2% (wt:vol) DSS in drinking water for 5 d (cellulose+control, n = 17; PF+control, n = 16; cellulose+DSS, n = 17; and PF+DSS, n = 16). Body weights and food and water intakes were collected daily from day 14 through day 22. Distal colon tissue was analyzed for histologic outcomes and changes in gene expression, and cecal contents were analyzed for SCFA concentrations. Data were analyzed by ANOVA, with repeated measures applied where necessary.

RESULTS

At day 5 post-DSS induction, cellulose+DSS mice exhibited a 2% reduction (P < 0.05) in body weight compared with PF+DSS and PF+ and cellulose+control mice. PF+DSS mice had greater (P < 0.05) cecal butyrate concentrations [24.5 μmol/g dry matter (DM)] than did cellulose+DSS mice (4.93 μmol/g DM). Mice fed PF+DSS had lower (P < 0.05) infiltration of leukocytes in the distal colon than did mice fed cellulose+DSS (mean histology scores of 1.22 and 2.30, respectively). Furthermore, mice fed cellulose+DSS exhibited 1.42, 11.5, 8.48, and 35.5 times greater (P < 0.05) colon mRNA expression of tumor necrosis factor α (Tnfa) and interleukin (Il) 1b, Il6, and Il17a, respectively, and 7.10 times greater (P < 0.05) expression of C-X-C motif ligand 1 (Cxc1) compared with mice fed PF+DSS.

CONCLUSIONS

These results suggest that PF fed to mice before and during DSS colitis attenuates inflammation, potentially through SCFA production; however, future studies are needed to understand the role of dietary fiber intake and immune activation.

OBJECTIVE

Orthodontic treatment induces dental tissue remodeling; however, dental pulp stem cell (DPSC)-mediated pulp micro-environmental alteration is still largely uncharacterized. In the present study, we identified elevated interleukin-17A (IL17A) in the dental pulp, which induced the osteogenesis of DPSCs after orthodontic force loading.

METHODS

Tooth movement animal models were established in Sprague-Dawley rats, and samples were harvested at 1, 4, 7, 14, and 21 days after orthodontic treatment loading. DPSC self-renewal and differentiation at different time points were examined, as well as the alteration of the microenvironment of dental pulp tissue by histological analysis and the systemic serum IL17A expression level by an ELISA assay. In vitro recombinant IL17A treatment was used to confirm the effect of IL17A on the enhancement of DPSC self-renewal and differentiation.

RESULTS

Orthodontic treatment altered the dental pulp microenvironment by activation of the pro-inflammatory cytokine IL17A in vivo. Orthodontic loading significantly promoted the self-renewal and differentiation of DPSCs. Inflammation and elevated IL17A secretion occurred in the dental pulp during orthodontic tooth movement. Moreover, in vitro recombinant IL17A treatment mimicked the enhancement of the self-renewal and differentiation of DPSCs.

CONCLUSIONS

Orthodontic treatment enhanced the differentiation and self-renewal of DPSCs, mediated by orthodontic-induced inflammation and subsequent elevation of IL17A level in the dental pulp microenvironment.

Two M5.1 and M15.2 B complex congenic lines of Fayoumi chickens were evaluated for body weight loss and faecal oocyst counts as parameters of avian coccidiosis. M5.1 chickens exhibited resistance to E. maxima compared with M15.2. To correlate the differential responses of the M5.1 and M15.2 lines to E. maxima infection with cellular immune responses, the expression levels of mRNAs encoding 14 immune-related molecules were measured by quantitative RT-PCR in intestinal intraepithelial lymphocytes (IELs) and splenocytes at 0, 3, 4, and 5 days following parasite infection. Intestinal IELs from M5.1 chickens expressed higher levels of transcripts encoding interferon gamma (IFNG), interleukin-lbeta (1L1B), IL6, IL8, IL12, IL15, IL17A, inducible nitric oxide synthase (iNOS), and lipopolysaccharide-induced tumour necrosis a factor (LITAF), and lower levels of mRNAs for IFNA, IL10, IL17D, NK-lysin (NKL), and tumour necrosis factor superfamily 15 (TNFSF15) at 3 days post infection, compared with the M15.2 line. In the spleen, E. maxima infection was associated with higher expression levels of IFNA, and IL15 and lower levels of IL6, IL17D, and IL12 in M5.1 compared to M15.2 birds. Using an intestinal IEL cDNA microarray, the differential dynamics of gene expression in the gut of M5.1 and M15.2 chickens following experimental coccidiosis were evident. In particular, the genes encoding lymphotactin and parathymosin were expressed at significantly higher levels in M5.1 compared with M15.2 line chickens. In conclusion, genetic determinants within the chicken major histocompatibility complex (MHC) B complex influence resistance to E. maxima infection by controlling the local and systemic expression of immune-related cytokine and chemokine genes.

Streptococcus pyogenes is the causative agent of numerous diseases ranging from benign infections (pharyngitis and impetigo) to severe infections associated with high mortality (necrotizing fasciitis and bacterial sepsis). As with other bacterial infections, there is considerable interest in characterizing the contribution of interleukin-17A (IL-17A) responses to protective immunity. We here show significant il17a up-regulation by quantitative real-time PCR in secondary lymphoid organs, correlating with increased protein levels in the serum within a short time of S. pyogenes infection. However, our data offer an important caveat to studies of IL-17A responsiveness following antigen inoculation, because enhanced levels of IL-17A were also detected in the serum of sham-infected mice, indicating that inoculation trauma alone can stimulate the production of this cytokine. This highlights the potency and speed of innate IL-17A immune responses after inoculation and the importance of proper and appropriate controls in comparative analysis of immune responses observed during microbial infection.

BACKGROUND

Protein expression is disturbed in the psoriatic stratum corneum (SC). Noninvasive methods for the description of pathophysiological changes and drug profiling in psoriasis are desirable.

OBJECTIVE

Undertake large-scale noninvasive protein expression studies in psoriatic SC to identify biomarkers of pathophysiological processes and use them for drug profiling.

METHODS

Psoriatic SC was harvested through repetitive tape-stripping. Nonlesional and lesional SC, as well as vehicle-treated and drug-treated lesional SC samples were collected. Protein extracts from nonlesional and lesional skin biopsies were used for comparison. Calcipotriol-betamethasone (CB) was used as a reference medication. Proteins extracted from pooled tape strips were quantified using mass spectrometry (MS), Western blotting, enzyme-linked immunosorbent assay and Luminex technologies.

RESULTS

MS-based methods identified 140 proteins differentially expressed in psoriatic SC. Epidermis development, glycolysis, regulation of apoptosis, cytoskeleton organization and peptide cross-linking were modulated, all reflecting perturbed epidermal differentiation. Using antibody-based techniques, increased levels of sICAM1, of CXCL1- and CXCL8-attracting neutrophils, of CXCL10- and CCL4-attracting T helper (Th) 1 cells, and of CCL2- and CCL4-attracting monocytes and dendritic cells were observed. Quantification of the Th1 and Th17 markers tumour necrosis factor, interleukin (IL) 12B, IL17A and IL17F in lesional SC was successful, while the Th2 cytokines IL4, IL5 and IL13, not involved in the disease process, were not detected. The pruritic cytokine IL31 was detected in lesional SC. CXCL1, CXCL8, CXCL10 and sICAM were used to investigate disease remission, ranking three topical treatments according to their known clinical efficacy.

CONCLUSIONS

Protein biomarker quantification in psoriatic SC detects key pathophysiological mechanisms and enables noninvasive drug profiling in translational medicine settings.

BACKGROUND

Recent studies have revealed the pivotal role of Th17 cells and interleukin-17 (IL-17) in plaque psoriasis development and treatment outcome. The IL-17 family consists of 6 structurally related cytokines (IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, IL-17F), of which IL-17A and IL-17F mediate similar biological effects.

OBJECTIVE

The aim of this study was to evaluate an association between the IL17A (-197G>A; rs2275913) and IL17F (rs763780: T>C; rs11465553: G>A; rs2397084: T>C) polymorphisms with psoriasis susceptibility as well as response to topical and combined topical with narrow-band ultraviolet B (NB-UVB) therapy in a Polish population.

METHODS

Association study involving 407 psoriasis patients and 205 healthy controls. Treatment efficacy was analyzed in 207 patients with mild psoriasis (Psoriasis Area and Severity Index; PASI 3-12) and moderate psoriasis (PASI 12-18), who were randomly subjected to topical or combined topical and NB-UVB treatment. The polymorphisms were evaluated by RT-PCR.

RESULTS

No statistically significant differences between psoriasis patients and controls were found in the frequency of the evaluated IL17A and IL17F genotypes and haplotypes. The IL17A or IL17F polymorphisms were not associated with treatment outcome measures: efficacy of treatment at the eighth week of the study and PASI change after topical or combined topical and NB-UVB therapy. However, IL17F rs2397084 variant allele C carriers required a significantly higher number of NB-UVB irradiations in comparison to TT homozygotes (15.5 ± 11.4 vs. 11.1 ± 11.9, p = 0.047) to produce a positive clinical response.

CONCLUSIONS

It can be stated that the IL17A and IL17F polymorphisms are not markers of susceptibility to psoriasis. However, the IL17F polymorphism may affect the response to NB-UVB therapy.

UNASSIGNED

T helper 17 [Th17] cells are crucially involved in the immunopathogenesis of inflammatory bowel diseases in humans. Nevertheless, pharmacological blockade of interleukin 17A [IL17A], the Th17 signature cytokine, yielded negative results in patients with Crohn's disease [CD], and attempts to elucidate the determinants of Th17 cells' pathogenicity in the gut have so far proved unsuccessful. Here, we aimed to identify and functionally validate the pathogenic determinants of intestinal IL-17-producing T cells.

UNASSIGNED

In vivo-generated murine intestinal IL-17-producing T cells were adoptively transferred into immunodeficient Rag1-/- recipients to test their pathogenicity. Human IL-17, IFNγ/IL-17, and IFNγ actively secreting T cell clones were generated from lamina propria lymphocytes of CD patients. The pathogenic activity of intestinal IL-17-producing T cells against the intestinal epithelium was evaluated.

UNASSIGNED

IL-17-producing cells with variable colitogenic activity can be generated in vivo using different experimental colitis models. The pathogenicity of IL-17-secreting cells was directly dependent on their IFNγ secretion capacity, as demonstrated by the reduced colitogenic activity of IL-17-secreting cells isolated from IFNγ-/- mice. Moreover, IFNγ production is a distinguished attribute of CD-derived lamina propria Th17 cells. IFNγ secretion by CD-derived IL-17-producing intestinal clones is directly implicated in the epithelial barrier disruption through the modulation of tight junction proteins.

UNASSIGNED

Intestinal Th17 cell pathogenicity is associated with IFNγ production, which directly affects intestinal permeability through the disruption of epithelial tight junctions.

Primary immune thrombocytopenia (ITP) is an autoimmune disorder. Interleukin-35 (IL35) can suppress T cell proliferation and elicit the development of inducible regulatory T cells (Tregs). Previous studies have shown decreased plasma IL35 levels and dysfunctional T cells in patients with ITP. In this study, we determined whether decreased IL35 levels correlate with T cell dysfunction in ITP patients. Plasma IL35 levels were found to be lower in ITP patients than in healthy controls, were positively correlated with platelet levels and the percentage of peripheral circulating Tregs, and negatively correlated with the levels of T helper-1 cells in ITP patients. We also evaluated the effects of IL35 on cytokines contributing to T cell proliferation. IL35 promoted the secretion of interleukin 10 (IL10) and transforming growth factor-β1 but reduced the levels of interferon-γ and IL17A (also termed IL17). Moreover, IL35 inhibited the proliferation of CD4+ and CD8+ T cells but induced the differentiation and proliferation of Tregs in ITP. In summary, IL35 appears to contribute to the loss of immunological self-tolerance in ITP patients by modulating T cells and immunoregulatory cytokines.

This study was conducted to explore the anti-inflammatory effect of Jungia sellowii (Asteraceae) using a murine model of pleurisy induced by carrageenan (Cg). This plant is used in southern Brazil to treat inflammatory diseases. J. sellowii leaves were extracted with ethanol/water to obtain the crude extract (CE), which was fractionated with different solvents, yielding n-hexane (Hex), dichloromethane (DCM), ethyl acetate (EtOAc) and n-butanol (BuOH) fractions, and aqueous fraction (Aq). The major compounds succinic acid (SA) and lactic acid (LA) were isolated from Aq fraction, and their structures were determined by (1)H and (13)C NMR. Pleurisy was induced by Cg (Saleh et al. 1996). The leukocytes, exudation, myeloperoxidase (MPO) and adenosine-deaminase (ADA) activities, metabolites of nitric oxide (NO x ) levels, protein levels and mRNA expression for interleukin 1 beta (IL-1β), tumour necrosis factor alpha (TNF-α), interleukin 17A (IL17A) and inducible of nitric oxide synthase (iNOs), and p65 protein phosphorylation (NF-κB) were analysed 4 h after pleurisy induction. Animals pre-treated with CE, BuOH, Aq, SA, or LA inhibited leukocytes, exudation, MPO and ADA activities, NO x , IL-1β, TNF-α, and IL-17A levels, and the mRNA expression for IL-1β, TNF-α, IL-17A, iNOS, and p65 protein phosphorylation (NF-κB) (p < 0.05). Our study demonstrated that J. sellowii can protect against inflammation induced by Cg by decreasing the leukocytes and exudation. Its effects are related to the decrease of either proinflammatory cytokines and/or NO x . The isolated compounds SA and LA may play an important role in this anti-inflammatory action by inhibiting all the studied parameters. The anti-inflammatory properties of these compounds are due to the downregulation of NF-κB.

Epigenetic modifications, such as posttranslational modifications of histones, play an important role in gene expression and regulation. These modifications are in part mediated by the Trithorax group (TrxG) complex and the Polycomb group (PcG) complex, which activate and repress transcription, respectively. We herein investigate the role of Menin, a component of the TrxG complex in T helper (Th) cell differentiation and show a critical role for Menin in differentiation and maintenance of Th17 cells. Menin(-/-) T cells do not efficiently differentiate into Th17 cells, leaving Th1 and Th2 cell differentiation intact in in vitro cultures. Menin deficiency resulted in the attenuation of Th17-induced airway inflammation. In differentiating Th17 cells, Menin directly bound to the Il17a gene locus and was required for the deposition of permissive histone modifications and recruitment of the RNA polymerase II transcriptional complex. Interestingly, although Menin bound to the Rorc locus, Menin was dispensable for the induction of Rorc expression and permissive histone modifications in differentiating Th17 cells. In contrast, Menin was required to maintain expression of Rorc in differentiated Th17 cells, indicating that Menin is essential to stabilize expression of the Rorc gene. Thus, Menin orchestrates Th17 cell differentiation and function by regulating both the induction and maintenance of target gene expression.

BACKGROUND

Key factors for successful porous polyethylene (PPE) implantation are rapid vascularization and low inflammatory response. Dermal fibroblasts produce a variety of pro-angiogenic and immunmodulatory factors.

OBJECTIVE

The aim of this tissue engineering study was to investigate whether coating PPE implants with dermal fibroblasts in vitro is sustainable in vivo and whether the kinetics of blood vessel ingrowth and immunological responses are hereby affected.

METHODS

PPE implants were cultured with syngeneic GFP-transfected dermal fibroblasts. Cells on the biomaterial were quantified before implantation into dorsal skinfold chamber preparations of C57Bl/6 mice. Uncoated implants served as controls. Angiogenic activity and leukocyte-endothelial cell interactions were repeatedly analyzed. After 10 days, mechanical integration was measured and surviving fluorescently labeled fibroblasts were quantified. Expression of inflammatory cytokines was assessed by quantitative real time-reverse transcription PCR.

RESULTS

PPE implants were successfully coated with dermal fibroblasts in vitro and 69% of the cells were still detectable at the end of observation. Angiogenic parameters increased during the observation period in both groups. IL-2, IL17A and IL-10 tended to be increased in coated implants, but did not affect leukocyte-endothelial cell interactions.

CONCLUSIONS

Dermal fibroblast-coating of porous polyethylene implants is feasible and sustainable in vivo. Alone it does not improve biocompatibility but may be beneficial in combination with specific growth factor supplements.