Elevated Serum Interleukin-23 Levels in Patients with Oral and Cutaneous Lichen Planus.

Lichen planus is considered a chronic inflammatory disease which affects different sites, such as the skin, mucous membranes, hair, and nails. Based on the evidence, a complex cytokine network plays a crucial role in lichen planus pathogenesis. The study was aimed at assessing the serum IL-23 levels in the patients with cutaneous and oral lichen planus compared to healthy controls. Method. The study included 30 cutaneous lichen planus patients, 20 oral lichen planus patients, and 33 control subjects. Five milliliters of peripheral blood was obtained from each patient, and the serum was separated. IL-23 levels were determined using the ELISA kit, and the data were analyzed using the Mann-Whitney test. Results. IL-23 levels in the patient serum with oral lichen planus (P value ≤ 0.001) were significantly higher than in controls. Furthermore, there were significant differences in IL-23 serum levels in the patients with cutaneous lichen planus compared to the healthy controls (P value ≤ 0.001). Moreover, IL-23 serum levels were statistically different between patients with cutaneous lichen planus and patients with oral lichen planus (P value ≤ 0.001). Based on the mean concentration of interleukin-23, IL-23 levels were higher in the patients with oral lichen planus than in the patients with cutaneous lichen planus. Conclusions. Elevated serum IL-23 levels in the patients with oral lichen planus may indicate that IL-23 plays a crucial role in the pathogenesis of oral lichen planus. However, more research is needed with a larger sample size.

IL-23/IL-17 axis and soluble receptors isoforms sIL-23R and sIL-17RA in patients with rheumatoid arthritis-presenting periodontitis.

BACKGROUND: Rheumatoid arthritis (RA) and periodontitis (P) are chronic inflammatory diseases characterized by joint and radiographic bone loss, respectively. IL-23 and IL-17 have an essential role in the immunopathogenesis of RA, and P. IL-23 stimulates Th17 cells through which produces IL-17, IL-21, and RANKL. IL-17 stimulates fibroblasts to produce RANKL, which initiates bone loss in the joints in RA and the periodontal tissue in periodontitis. The aim of this study was to determine the expression pattern of IL-23/IL-17 axis and soluble receptors isoforms sIL-23R and sIL-17RA of patients with RA presenting P (RAP). MATERIAL AND METHODS: Healthy subjects (HS) (n = 42), patients with P (n = 40), RA (n = 20), and patients with RAP (n = 40) were included. Plasma samples were obtained to evaluate the IL-23, IL-17A, sIL-23R, and sIL-17RA by ELISA technique. A nonparametric Mann-Whitney U test was used to compare the differences between groups. A Chi-square was used to compare gender, grade and stage of periodontitis, and DAS28-ESR between the groups. Spearman's rank correlation coefficient was used to study the association between the molecules and clinical parameters. RESULTS: IL-23 levels were increased in the RAP group, and lower sIL-23R levels were found in the RAP groups. However, IL-17A was lower in the P and RAP group but not in RA patients. RAP group showed a decrease IL-17A levels in advanced stages of the periodontal disease. CONCLUSION: These results suggest that IL-23 and IL-17A tend to downregulate their expression patterns when patients present both rheumatoid arthritis and periodontitis.

IL-38: A novel cytokine in systemic lupus erythematosus pathogenesis.

IL-38 is a newly identified cytokine that belongs to the IL-1 family. In our previous study, we found elevated plasma levels of IL-38 in patients with systemic lupus erythematosus (SLE). However, the clear relationship of IL-38 expression in plasma, peripheral blood mononuclear cells (PBMCs) and clinical and laboratory features needs elucidation. Additionally, we evaluated the possible role of IL-38 in regulating production of inflammatory cytokines in PBMCs in vitro. A pristane-induced murine lupus model was used to further demonstrate the effects of IL-38 on cytokines in vivo and discuss the significance of IL-38 in lupus development. The results showed that mRNA expression of IL-38 in PBMCs of patients with SLE was elevated compared with volunteers, and expression of IL-38 in both plasma and PBMCs was strongly related to clinical features, such as haematuria and proteinuria, and correlated with a SLEDAI score. Plasma levels of TNF-α, IL-1ß, IL-6 and IL-23 were elevated in patients with SLE and were related to plasma levels of IL-38. In vitro, PBMCs of patients with SLE stimulated with IL-38 showed a decreased expression of the four inflammatory cytokines compared with PBMCs of patients without treatment. Interestingly, IL-38 administration in lupus mice significantly reduced the development of lupus, such as reduced proteinuria, improved histological examinations of the kidneys and down-regulated inflammatory cytokines. In conclusion, IL-38 may suppress synthesis of pro-inflammatory cytokines and therefore regulate lupus pathogenesis.

High interleukin-18 and low FOXP3 mRNAs in peripheral blood of women with severe systemic lupus erythematosus: a cross-sectional study.

Gene expression analysis of peripheral blood cells may provide valuable information about the triggered molecular processes in systemic lupus erythematosus (SLE). The study aimed to quantify the mRNA in peripheral blood of seven target genes, including inflammatory cytokine genes (IL23A, IL12B, TNFA, IL18), and T regulatory-related genes (FOXP3, TGFB1, IL10) in patients with SLE and to correlate expression levels with disease activity and/or clinical manifestations. The relative quantification of target genes was performed using real-time polymerase chain reaction in peripheral blood obtained from 28 adult SLE females and 17 healthy women. The highest up-regulation in the blood of SLE patients was observed for IL23A with a median 9.54 (p < 0.0001), followed by TGFB1 (median: 2.07; p = 0.047) and IL10 (median: 1.84; p = 0.013). IL12B and TNFA were significantly down-regulated in patients compared to controls (median: 0.521; p = 0.0023, and median: 0.519; p = 0.0003, respectively). FOXP3 mRNA was lower among patients with higher degree of disease activity (median: 0.338; p = 0.029) and showed inverse correlation with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). IL18 mRNA correlated positively with the SLEDAI and was highly expressed during severe flares (median: 1.216; p = 0.021). IL18 up-regulation was associated with anti-dsDNA antibody positivity, while FOXP3 down-regulation with lupus nephritis. Our study pointed out the relationship of SLE disease activity and particular clinical manifestations with IL18 and FOXP3 expression, and the significant contribution of IL23A in the SLE immunopathogenesis. Hence, the peripheral blood cytokine mRNAs should be exploited as novel prognostic and diagnostic biomarkers.

Nonclinical safety of tildrakizumab, a humanized anti-IL-23p19 monoclonal antibody, in nonhuman primates.

Tildrakizumab (also known as MK-3222), is a high-affinity, humanized, immunoglobin G1κ monoclonal antibody targeting the p19 subunit of interleukin-23 recently approved for the treatment of moderate to severe plaque psoriasis in the US, Europe, and Australia. The safety profile of tildrakizumab was characterized in nonclinical studies using a pharmacologically relevant cynomolgus monkey model. In repeat-dose toxicity studies, cynomolgus monkeys were chronically treated with subcutaneous (SC) injections of 100 mg/kg of tildrakizumab every 2 weeks up to 9 months. Tildrakizumab was well tolerated, with no toxicological findings (including assessment of reproductive organs; hormonal effects; and cardiovascular, respiratory, and central nervous system function) at systemic exposures approximately 90 times higher than the recommended human dose of 100 mg. An embryofetal developmental study conducted in pregnant monkeys revealed no treatment-related effects to the developing fetus following SC administration of tildrakizumab 100 mg/kg. In a pre- and postnatal development study, 2 neonatal deaths due to potential viral infection at 100 mg/kg were considered of uncertain relationship to the treatment based on a lack of historical data on the occurrence of viral infection in neonate cynomolgus monkeys. The results of this comprehensive nonclinical safety program support the safe use of tildrakizumab.

Altered Treg and cytokine responses in RSV-infected infants.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and pneumonia in children under 1 y of age in the USA. The host immune response is believed to contribute to RSV-induced disease. We hypothesize that severe RSV infection in infants is mediated by insufficient regulation of the host immune response of regulatory T cells (Tregs) resulting in immunopathology. METHODS: Blood and nasal aspirates from 23 RSV-infected and 17 control infants under 1 y of age were collected. Treg frequencies were determined by flow cytometry from peripheral blood mononuclear cells. Analysis of 24 cytokines was measured by multiplex assay on nasal aspirates. RESULTS: We demonstrate that the frequency of activated Tregs is significantly reduced in the peripheral blood of RSV-infected infants compared with age-matched controls. Surprisingly, T helper (Th)17 related cytokines including interleukin (IL)-1ß, IL-17A, and IL-23 were associated with a reduction in clinical symptoms of respiratory distress. In addition, the amount of IL-33 protein in nasal washes, a cytokine important in maintaining Treg homeostasis in mucosal tissues, was decreased in RSV-infected children. CONCLUSION: These results suggest that decreased Treg numbers and an inability to properly control the host inflammatory response results in severe RSV infection.

Both interleukin-23A polymorphism and serum interlukin-23 expression are associated with Graves' disease risk.

Two independent Chinese cohorts were used to study the genetic association between the interleukin-23A (IL-23A) gene polymorphism (rs11171806) and susceptibility to Graves' disease (GD). The initial Shanghai cohort consisted of 712 unrelated patients with GD and 705 healthy control subjects, and the replication cohort from Xiamen Island included 433 patients with GD and 410 healthy control subjects. The serum concentration of IL-23 in GD patients was measured significantly higher than in health controls. Moreover in the subgroup analysis, higher concentrations of IL-23 were identified in patients of older age (⩾40 years) and female gender. We also performed an association study with the IL-23 gene polymorphism rs11171806 in both cohorts, in Shanghai cohorts, the frequencies of rs11171806 alleles were strongly different between Graves' disease patients (G 95.7% and A 4.3%) and healthy controls (G 97.7% and A 2.3%) (P=2.6×10(-3), OR=1.93 (95% CI: 1.25-2.97)), and in Xiamen cohorts, the proportion of individuals carrying the A allele of rs11171806 was the same significantly higher in Graves' disease patients than in controls [Graves' disease vs. control, 4.8% vs. 4.3%, OR=2.15 (95% CI: 1.23-3.79), P(allele)=6.3×10(-3)]. The distribution of rs11171806 genotype was also investigated in subgroups according to the age and gender. All of these findings suggested that IL-23 may play an important role in the development of GD, and the IL-23A gene is a genetic risk marker for GD in Han Chinese population.

Increased interleukin 23 (IL23) levels in schizophrenia patients treated with depot antipsychotic medication.

BACKGROUND: Schizophrenia is a mental disorder, where genetic and environmental factors contribute to disease onset and progression. The immune system appears to play a role in schizophrenia, where altered cytokines levels and autoantibodies have been described. Notably however, to our knowledge, IL23 levels have not before been measured in schizophrenia patients treated with depot medication. METHODS: We examined IL23 levels in serum samples obtained from patients with schizophrenia, treated with depot medication (n=35) compared with healthy controls (n=38) and correlated these levels with treatment time, patient age and illness severity. RESULTS: IL23 levels were raised in depot treated groups compared with healthy controls. No correlation was observed, however, between IL23 levels and treatment time, patient age or illness severity. CONCLUSIONS: IL23 levels are raised in schizophrenia patients prescribed with depot medication, supporting the role of aberrant cytokine signalling in schizophrenia.

Resistin-like molecule α promotes pathogenic Th17 cell responses and bacterial-induced intestinal inflammation.

Resistin-like molecule (RELM)α belongs to a family of secreted mammalian proteins that have putative immunomodulatory functions. Recent studies have identified a pathogenic role for RELMα in chemically induced colitis through effects on innate cell populations. However, whether RELMα regulates intestinal adaptive immunity to enteric pathogens is unknown. In this study, we employed Citrobacter rodentium as a physiologic model of pathogenic Escherichia coli-induced diarrheal disease, colitis, and Th17 cell responses. In response to Citrobacter, RELMα expression was induced in intestinal epithelial cells, infiltrating macrophages, and eosinophils of the infected colons. Citrobacter-infected RELMα(-/-) mice exhibited reduced infection-induced intestinal inflammation, characterized by decreased leukocyte recruitment to the colons and reduced immune cell activation compared with wild-type (WT) mice. Interestingly, Citrobacter colonization and clearance were unaffected in RELMα(-/-) mice, suggesting that the immune stimulatory effects of RELMα following Citrobacter infection were pathologic rather than host-protective. Furthermore, infected RELMα(-/-) mice exhibited decreased CD4(+) T cell expression of the proinflammatory cytokine IL-17A. To directly test whether RELMα promoted Citrobacter-induced intestinal inflammation via IL-17A, infected WT and IL-17A(-/-) mice were treated with rRELMα. RELMα treatment of Citrobacter-infected WT mice exacerbated intestinal inflammation and IL-17A expression whereas IL-17A(-/-) mice were protected from RELMα-induced intestinal inflammation. Finally, infected RELMα(-/-) mice exhibited reduced levels of serum IL-23p19 compared with WT mice, and RELMα(-/-) peritoneal macrophages showed deficient IL-23p19 induction. Taken together, these data identify a proinflammatory role for RELMα in bacterial-induced colitis and suggest that the IL-23/Th17 axis is a critical mediator of RELMα-induced inflammation.

Altered serum interleukin-17A and interleukin-23A levels may be associated with the pathophysiology and development of generalized anxiety disorder.

In recent times, the pathogenesis of generalized anxiety disorder (GAD) and the influence of pro- and anti-inflammatory cytokines on it have garnered considerable interest. Cytokine research, especially Th-17 cytokine research on GAD patients, is limited. Here, we aim to assess the role of interleukin-17A (IL-17A) and interleukin-23A (IL-23A) in the pathophysiology and development of GAD. This investigation included 50 GAD patients and 38 age-sex-matched healthy controls (HCs). A psychiatrist diagnosed patients with GAD and assessed symptom severity using the DSM-5 and the GAD-7 scales. The serum concentrations of IL-17A and IL-23A were determined using commercially available ELISA kits. GAD patients exhibited elevated levels of IL-17A (77.14 ± 58.30 pg/ml) and IL-23A (644.90 ± 296.70 pg/ml) compared to HCs (43.50 ± 25.54 pg/ml and 334.40 ± 176.0 pg/ml). We observed a positive correlation between disease severity and cytokine changes (IL-23A: r = 0.359, p = 0.039; IL-17A: r = 0.397, p = 0.032). These findings indicate that IL-17A and IL-23A may be associated with the pathophysiology of GAD. ROC analysis revealed moderately higher AUC values (IL-23A: 0.824 and IL-17A: 0.710), demonstrating their potential to discriminate between patients and HCs. Also, the sensitivity values of both cytokines were relatively higher (IL-23A: 80.49% and IL-17A: 77.27%). According to the present findings, there may be an association between peripheral serum levels of IL-17A and IL-23A and the pathophysiology and development of GAD. These altered serum IL-17A and IL-23A levels may play a role in directing the early risk of developing GAD. We recommend further research to ascertain their exact role in the pathophysiology and their performance as risk assessment markers of GAD.

Protective effect of interleukin-23A (IL23A) haplotype variants on type 1A diabetes mellitus in a Brazilian population.

The Interleukin 23 (IL-23) has a central role in autoimmunity. Allelic variants of p19 subunit of IL-23 (IL23A) and IL-23 receptor (IL23R) genes and increased IL-23 serum concentrations were associated with autoimmune diseases. We therefore searched for variants of IL23A and IL23R that could predispose to Type 1 diabetes (T1D). The coding regions and boundary intron sequences of IL23A were sequenced. Variants of IL23A and of IL23R were also genotyped. Pancreatic and extrapancreatic autoantibodies and IL-23 serum levels were determined. The cohort involved 370 patients with T1D and 351 healthy control subjects. We observed only one coding IL23A variant (rs11171806 G>A) out of the 6 described in databases. As the G alleles of rs11171806 and rs2066808 variants of IL23A gene were in strong linkage disequilibrium (D'=-0.825 for controls, p<2.0 × 10(-6) and D'=-0.902, p<2.0 × 10(-17) for patients), further analyses were performed with the haplotypes. The GG haplotype was more frequent in controls (16.7%) than in T1D patients (9.5%), conferring a protection to T1D (OR=0.53; pc=0.0003). No association was found between IL23A allelic variants with age at diagnosis of diabetes, C-peptide levels or frequency of autoantibodies. IL23R variants (rs10889677 and rs11209026) frequency and IL-23 serum concentrations were similar between groups. The GG haplotype of lL23A variants (rs11171806 and rs2066808) was protective against T1D. IL23R variants (rs11209026 and rs10889677) were not associated with T1D. IL-23 serum concentrations did not differ between groups.

[Expression of Th17 and IL-23 in Peripheral Blood and Their Relationship with Immunophenotype in Patients with Acute Myeloid Leukemia].

OBJECTIVE: To observe the expression of helper T cells 17(Th17), interleukin 23 (IL-23) in peripheral blood in patients with acute myeloid leukemia (AML), to analyze the relationship between Th17, IL-23 in peripheral blood and immunophenotype. METHODS: 105 patients with AML in the hospital from January 2019 to January 2021 were prospectively selected as the research subjects, the expression of Th17 and IL-23 in peripheral blood of patients with AML was detected by flow cytometry; immunophenotype was detected and counted. The relationship between the expression of Th17, IL-23 in peripheral blood and immunophenotype of AML patients was analyzed. Draw ROC curve and analyze the predictive value of Th17 and IL-23 expression in peripheral blood to immunophenotype. RESULTS: The immunophenotype results of AML patients showed that myeloid antigen, lymphoid antigen and hematopoietic stem/progenitor cell marker antigen were positive expressed for various antigens in 105 AML patients, in myeloid antigens, CD13+ accounted for the highest proportion (93.33%), in lymphoid antigens, CD56+ accounted for the highest proportion (32.38%), and in hematopoietic stem/progenitor cell marker antigens, CD38+ accounted for the highest proportion (68.57%). The expression of Th17 in peripheral blood of AML patients with CD56+, CD7+, CD34+ and human leukocyte antigen DR+(HLA-DR+) were higher than that of AML patients with CD56-, CD7-, CD34-, HLA-DR-, the expression of IL-23 in peripheral blood of AML patients with CD56+, CD34+ and HLA-DR+ were higher than that of AML patients with CD56-, CD34-, HLA-DR-, the differences were statistically significant (P<0.05); compared the expression of Th17 and IL-23 in peripheral blood between other antibody positive and negative patients, there was no statistical significant difference (P>0.05). Logistic regression analysis showed that the high expression of Th17 in patients with AML was related to the positive expression of CD56, CD7, CD34 and HLA-DR in the detection of immunophenotype, the high expression of IL-23 was related to the positive expression of CD56, CD34 and HLA-DR in the detection of immunophenotype. The ROC curve showed that the AUC of expression levels of Th17 and IL-23 in peripheral blood alone and in combination for predicting CD56+, CD34+, HLA-DR+ and Th17 in peripheral blood for predicting CD7+ were mostly 0.5-0.7, which had certain predictive value, but the predictive performance was low. CONCLUSION: Myeloid antigen, lymphoid antigen and hematopoietic hematopoietic stem/progenitor cell marker antigen are positive expressed for various antigens in AML patients, the high expression of Th17 in peripheral blood of AML patients is related to the positive expression of CD56, CD7, CD34 and HLA-DR in detection of immunophenotyping, the high expression of IL-23 is related to the positive expression of CD56, CD34 and HLA-DR in the detection of immunophenotype.

Mucosal IL23A expression predicts the response to Ustekinumab in inflammatory bowel disease.

BACKGROUND: Biologics against tumor necrosis factor-α (TNF) and the p40 subunit of interleukin (IL)-12 and IL-23 are increasingly used in inflammatory bowel disease (IBD) treatment. However, information on response prediction to these agents is limited. Thus, we aimed to identify factors for IBD treatment response prediction. METHODS: We conducted a retrospective study in 33 IBD subjects for anti-TNF and a prospective study of 23 IBD and 11 non-IBD subjects for ustekinumab (UST). Mucosal biopsy specimens were obtained before treatment with biologics. The expression of 18 immune-related genes encoding representative cytokines and transcription factors was analyzed by quantitative polymerase chain reaction. RESULTS: There was no difference between the treatment-resistant and -sensitive groups with regard to clinical characteristics. A higher expression of oncostatin M (OSM) and its receptor OSMR in the intestinal mucosa was most strongly associated with anti-TNF resistance, whereas lower IL23A expression was most strongly associated with UST resistance. In addition to the absolute expression levels of genes, concordant or discordant expression patterns of particular gene sets were associated with treatment sensitivity and resistance. CONCLUSIONS: The association of anti-TNF resistance and mucosal OSM and OSMR expression was consistent with the results of a previous study in a European cohort. Our observation that IBD subjects with higher mucosal IL23A expression were more likely to achieve remission by UST has not been previously reported. The response to biologics may thus be predicted in IBD patients through the analysis of mucosal gene expression levels and patterns.

Differentiation imbalance of Th1/Th17 in peripheral blood mononuclear cells might contribute to pathogenesis of Hashimoto's thyroiditis.

T helper 17(Th17) cell is a new subset of CD4(+) T cells that produce a proinflammatory cytokine interleukin-17 (IL-17). Th17 cells have recently been shown to play a critical role in many autoimmune diseases that had previously been thought to be Th1 dominant. Although Hashimoto's thyroiditis (HT) was thought to be a Th1-type disease, the contributions of Th17 cells to the pathogenesis remain unclear. In this study, we investigated the expression levels of Th1/Th17 cell-associated factors in peripheral blood mononuclear cells (PBMC) and plasma from patients with HT by quantitative real-time polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA). Our results showed that the expression levels of Th1 cells-related T-bet and interferon-gamma (IFN-gamma) mRNA in PBMC from HT significantly decreased. However, the mRNA of Th17 coherent retinoic acid-related orphan nuclear receptor gamma t (RORgammat) and IL-17 in patients with HT increased. In addition, a negative correlation between T-bet and RORgammat mRNA expression was found in patients with HT, and the similar phenomena also appeared on the levels of mRNA and plasma concentration between IFN-gamma and IL-17. It suggested that Th17 cells rather than Th1 cells predominated among patients suffering from HT, and Th17 cells might be involved in the pathogenesis of HT.

Anti-cyclic citrullinated peptide antibodies and IL-23p19 in psoriatic arthritis.

BACKGROUND: Anti-cyclic citrullinated peptide antibodies (anti-CCP) are reported to be found in 5-13% of patients with psoriatic arthritis (PsA). However, whether anti-CCP-positive PsA patients and rheumatoid arthritis (RA) patients have a similar pathophysiological background still remains uncertain. OBJECTIVE: To determine the prevalence of anti-CCP antibodies in patients with PsA and characterize these anti-CCP-positive patients of PsA. METHODS: We measured the serum levels of the anti-CCP antibodies in patients with PsA (n=16), psoriasis (n=15), RA (n=9) and healthy controls (n=11). Serum levels of rheumatoid factor (RF), matrix metalloproteinase-3 (MMP-3), cartilage oligomeric matrix protein (COMP), interleukin (IL)-23p19 and IL-12p40 were also measured in all the samples. RESULTS: Two of the 16 PsA patients (13%) were positive for anti-CCP antibodies with high titers of RF. However, the serum IL-23p19 levels were two orders of magnitude higher in the anti-CCP-positive PsA patients as compared with those in the RA patients and anti-CCP-negative PsA patients. No significant elevation of the serum levels of MMP-3, COMP and IL-12p40 was found in these patients. CONCLUSION: Thirteen percent of the PsA patients were positive for anti-CCP. These patients do not fulfill the American College of Rheumatology (ACR) classification criteria for RA so far. Furthermore, they showed the typical clinical features of PsA rather than those of RA. Although anti-CCP-positive PsA patients may possibly be have a risk of developing RA, we propose that these patients be classified, for the moment, into a independent subtype of PsA, as a different entity from RA.

High expression of Foxp3, IL-23p19 and survivin mRNA in colorectal carcinoma.

INTRODUCTION: Cytokines have been suggested to both modulate anti-tumor responses and promote tumor growth. MATERIALS AND METHODS: We analyzed the expression of pro-inflammatory IL-12p35, IL-12p40, IL-23p19, anti-inflammatory IL-10, antiapoptotic factor survivin, and transcription factors-RelA, c-Jun, and Foxp3 mRNA in patients' blood, colon carcinoma tissue, and in normal mucosal tissue by real-time polymerase chain reaction. The quantity determination of serum IL-12p40, IL-23, and IL-10 was performed by enzyme-linked immunosorbent assay. RESULTS: We observed significantly higher levels in patients for all three analyzed cytokines, with IL-23 concentration change being the highest. We detected the greatest upregulation of IL-23p19, Foxp3 and survivin mRNA in colorectal carcinomas than normal mucosa. A statistically significant upregulation of IL-12p40, IL-10, and c-Jun mRNA but not for IL-12p35 and RelA mRNA in tumor tissue comparing to normal tissue was also established. CONCLUSIONS: In conclusion, we show a characteristic gene expression profile combining markers associated with inhibition of anti-tumor immune response (Foxp3, IL-10), inhibition of apoptosis (survivin), and induction of the cytokines with protumoral activity as IL-12p40 and IL-23p19 (IL-23) in the colorectal tumor tissue but not in peripheral blood of patients.

Effect of 50-Hz Magnetic Fields on Serum IL-1ß and IL-23 and Expression of BLIMP-1, XBP-1, and IRF-4.

Investigations demonstrated that magnetic fields (MFs) change cytokine production and expression of some immune system genes. This alteration can affect the immune system function and may lead to some diseases. Therefore, this study investigated two important inflammatory cytokines, i.e., IL-1ß and IL-23 at two phases of pre- and post-immunization of the immune system. In addition, the expressions of three important genes in the humoral immunity, i.e., B lymphocyte-induced maturation protein-1 (BLIMP-1), X-box-binding protein-1 (XBP-1), and interferon regulatory factor-4 (IRF-4) were evaluated at post-immunization phase. Eighty adult male rats were divided into four experimental groups and a control. The experimental groups were exposed to 50 -Hz MFs with magnetic flux densities of 1, 100, 500, and 2000 µT, 2 h/day for 2 months. The animals were injected by human serum albumin (100 µg/rat) on days 31, 44, and 58 of exposure. The cytokine levels in serum were measured with enzyme-linked immunosorbent assay (ELISA), and the expression of genes was evaluated with reverse transcription quantitative polymerase chain reaction (RT-qPCR). Serum IL-1ß was decreased at pre-immunization phase after exposure to 1 and 100 µT of 50-Hz MFs. In contrast, serum IL-23 was increased at post-immunization phase in 100 µT group. No change was observed in serum IL-1ß and IL-23 in each group at pre-immunization phase compared with post-immunization. Furthermore, exposure to 100 µT downregulated expression of BLIMP-1, XBP-1, and IRF-4. In conclusion, exposure to 50-Hz MFs may decrease inflammation at short time and increase it at longer time exposures. In addition, 50-Hz MF exposure may decrease the humoral immune responses. It seems that 50-Hz MFs cause more alteration in immune system function at lower densities (100 µT).

NET Formation in Bullous Pemphigoid Patients With Relapse Is Modulated by IL-17 and IL-23 Interplay.

Background: DNA extracellular traps (ETs), released by neutrophils (NETs), or eosinophils (EETs), play a pathogenic role in several autoimmune disorders. However, to date, NETs have never been investigated in bullous pemphigoid (BP) with respect to clinical and immunological activities, both at baseline and at time of relapse which have been characterized with specific IL-17 and IL-23 patterns. Objective: We sought to assess whether ETs were associated with BP as well as the relative contribution of IL-17 axis cytokines to NET induction. Methods: Skin biopsy specimens were obtained from 11 patients with BP. Immuno-detection of neutrophils and eosinophils combined to DNA staining allowed us to investigate the in-situ presence of NETs and EETs using confocal scanning microscopy. NETs release was evaluated ex vivo by stimulating polymorphonuclear cells from BP patients with BP biological fluids in presence of IL-17A and IL-23 or of glucocorticoids. Results: At baseline, ETs were observed in BP lesions at the site of dermal-epidermal cleavage. Despite an important infiltrate of eosinophils, ETs were essentially associated with neutrophils in situ and were not related to BP clinical activity at diagnosis. In situ observation of NETs was associated in 6 among 8 patients with serum capacity of NET induction. Notably both blister fluid and sera from BP patients at diagnosis and at time of relapse could induce NET formation ex vivo. In contrast, a longitudinal investigation showed a decrease of NET formation with time of treatment in patients undergoing remission. Mimicking relapse, complementation of sera from BP patients with ongoing remission with either IL-17A or IL-23 increased NET formation. Conversely, IL-17A inhibited NET formation induced by serum from BP patients with relapse supplemented or not with IL-23. Finally, glucocorticoids also inhibited NET formation ex vivo in BP. Conclusion: NET formation is an associated phenomenon with BP. Furthermore, we showed that IL-23 favored NET formation, whereas the effects of IL-17A are environment dependent. Indeed, IL-17A displayed a protective effect on NET formation when associated with IL-23, showing for the first-time differential effects of these two cytokines in BP.

Colitis-Induced Th17 Cells Increase the Risk for Severe Subsequent Clostridium difficile Infection.

Clostridium difficile infection (CDI) is the number one hospital-acquired infection in the United States. CDI is more common and severe in inflammatory bowel disease patients. Here, we studied the mechanism by which prior colitis exacerbates CDI. Mice were given dextran sulfate sodium (DSS) colitis, recovered for 2 weeks, and then were infected with C. difficile. Mortality and CDI severity were increased in DSS-treated mice compared to controls. Severe CDI is dependent on CD4+ T cells, which persist after colitis-associated inflammation subsides. Adoptive transfer of Th17 cells to naive mice is sufficient to increase CDI-associated mortality through elevated IL-17 production. Finally, in humans, the Th17 cytokines IL-6 and IL-23 associate with severe CDI, and patients with high serum IL-6 are 7.6 times more likely to die post infection. These findings establish a central role for Th17 cells in CDI pathogenesis following colitis and identify them as a potential target for preventing severe disease.

The prevalence of Th17 cells in patients with gastric cancer.

Th17 cells have emerged as an important mediator in inflammatory and autoimmune diseases. However, recent studies suggest a potential impact of Th17 cells on tumor. The current study was designed to investigate the possible involvement of Th17 cells in gastric cancer. Compared with healthy volunteers, patients with gastric cancer had a higher proportion of Th17 cells in peripheral blood. Notably, the increased prevalence of Th17 cells was associated with clinical stage. In addition, increased populations of Th17 cells were present in tumor-draining lymph nodes with advanced disease. Furthermore, the mRNA expression levels of Th17-related factors (IL-17, IL-23p19, and RORC) in tumor tissues and the serum concentrations of IL-17 and IL-23 cytokines were significantly increased in patients with advanced gastric cancer. The results indicate that Th17 cells may contribute to gastric cancer pathogenesis.