IL-17F Expression Research Articles

Interleukin-17 family cytokines in protective immunity against infections: role of hematopoietic cell-derived and non-hematopoietic cell-derived interleukin-17s.

Interleukin-17 family cytokines, consisting of six members, participate in immune response in infections and autoimmune and inflammatory diseases. The prototype cytokine of the family, IL-17A, was originally identified from CD4+ T cells which are now termed Th17 cells. Later, IL-17A-producing cells were expanded to include various hematopoietic cells, namely CD8+ T cells (Tc17), invariant NKT cells, γδ T cells, non-T non-B lymphocytes (termed type 3 innate lymphoid cells) and neutrophils. Some IL-17 family cytokines other than IL-17A are also expressed by CD4+ T cells: IL-17E by Th2 cells and IL-17F by Th17 cells. IL-17A and IL-17F induce expression of pro-inflammatory cytokines to induce inflammation and anti-microbial peptides to kill pathogens, whereas IL-17E induces allergic inflammation. However, the functions of other IL-17 family cytokines have been unclear. Recent studies have shown that IL-17B and IL-17C are expressed by epithelial rather than hematopoietic cells. Interestingly, expression of IL-17E and IL-17F by epithelial cells has also been reported and epithelial cell-derived IL-17 family cytokines shown to play important roles in immune responses to infections at epithelial sites. In this review, we summarize current information on hematopoietic cell-derived IL-17A and non-hematopoietic cell-derived IL-17B, IL-17C, IL-17D, IL-17E and IL-17F in infections and propose functional differences between these two categories of IL-17 family cytokines.

Downregulation of common cytokine receptor γ chain inhibits inflammatory responses in macrophages stimulated with Riemerella anatipestifer

Th17-cell-mediated inflammation is affected by the soluble form of common cytokine receptor γ chain (γc). We previously suggested that inflammatory cytokines including interleukin (IL)-17A are associated with Riemerella anatipestifer infection, which a harmful bacterial pathogen in ducks. Here, the expression profiles of membrane-associated γc (duγc-a) and soluble γc (duγc-b) in R. anatipestifer-stimulated splenic lymphocytes and macrophages, and in the spleens and livers of R. anatipestifer-infected ducks, were investigated. In vitro and in vivo results indicated that the expression levels of both forms of γc were increased, showing that marked increases were detected in the expression of the duγc-b form rather than the duγc-a form. Treatment with γc-specific siRNA downregulated mRNA expression of Th17-related cytokines, including IL-17A and IL-17F, in duck splenic macrophages stimulated with R. anatipestifer, whereas the expressions of interferon (IFN)-γ and IL-2 were enhanced. The results showed that the upregulation of γc, especially the duγc-b form, was associated with expression of Th17-related cytokines during R. anatipestifer infection.

Newer treatments of psoriasis regarding IL-23 inhibitors, phosphodiesterase 4 inhibitors, and Janus kinase inhibitors.

The rapid progress of genetic engineering furthermore opens up new prospects in the therapy of this difficult-to-treat disease. IL-23 inhibitors, phosphodiesterase 4 (PDE4) inhibitors, and Janus kinase (JAK) inhibitors are currently encouraging further research. Two drugs which are IL-23 inhibitors are now in phase III of clinical trials. The aim of the action of both drugs is selective IL-23 inhibition by targeting the p19 subunit. Guselkumab is a fully human monoclonal antibody. Tildrakizumab is a humanized monoclonal antibody, which also belongs to IgG class and is targeted to subunit p19 of interleukin 23 (IL-23). Phosphodiesterase inhibitors exert an anti-inflammatory action and their most common group is the PDE4 family. PDE4 inhibits cAMP, which reduces the inflammatory response of the pathway of Th helper lymphocytes, Th17, and type 1 interferon which modulates the production of anti-inflammatory cytokines such as IL-10 interleukins. The Janus kinase (JAK) signaling pathway plays an important role in the immunopathogenesis of psoriasis. Tofacitinib suppresses the expression of IL-23, IL-17A, IL-17F, and IL-22 receptors during the stimulation of lymphocytes. Ruxolitinib is a selective inhibitor of JAK1 and JAK2 kinases and the JAK-STAT signaling pathway. This article is a review of the aforementioned drugs as described in the latest available literature.

RORγt-expressing cells attenuate cardiac remodeling after myocardial infarction.

AimsRetinoic acid receptor-related orphan nuclear receptor γt (RORγt) is a transcriptional factor responsible for IL-17-producing T-cell differentiation. Although it was demonstrated that RORγt plays essential roles in the onset of autoimmune myocarditis, pathophysiological significance of RORγt in cardiac remodeling after myocardial infarction (MI) remains to be fully elucidated.Methods and resultsMI was generated by ligating coronary artery. The expression of RORγt and IL-17A transcripts increased in murine hearts after MI. Additionally, immunohistochemical staining revealed that RORγt-expressing cells infiltrated in the border zone after MI. Flow cytometric analysis showed that RORγt-expressing cells were released from the spleen at day 1 after MI. Though RORγt-expressing cells in spleen expressed γδTCR or CD4, γδTCR+ cells were major population of RORγt-expressing cells that infiltrated into post-infarct myocardium. To address the biological functions of RORγt-expressing cells in infarcted hearts, we used mice with enhanced GFP gene heterozygously knocked-in at RORγt locus (RORγt+/- mice), which physiologically showed reduced expression of RORγt mRNA in thymus. Kaplan-Meier analysis showed that MI-induced mortality was higher in RORγt+/- mice than wild-type (WT) mice. Masson’s trichrome staining demonstrated that cardiac injury was exacerbated in RORγt+/- mice 7 days after MI (Injured area: RORγt+/-; 42.1±6.5%, WT; 34.0±3.7%, circumference of injured myocardium: RORγt+/-; 61.8±4.8%, WT; 49.6±5.1%), accompanied by exacerbation of cardiac function (fractional shortening: RORγt+/-; 32.9±2.9%, WT; 38.3±3.6%). Moreover, immunohistochemical analyses revealed that capillary density in border zone was significantly reduced in RORγt+/- mice after MI, compared with WT mice, associated with the reduced expression of angiopoietin 2. Finally, the mRNA expression of RORγt, IL-17A, IL-17F and IL-23 receptor (IL-23R) mRNA and protein expression of IL-10 were decreased in RORγt+/- hearts.ConclusionsHeterozygous deletion of RORγt gene resulted in aggravated cardiac remodeling, accompanied by reduced capillary density, after MI, suggesting that RORγt-expressing cells contribute to tissue repair in infarcted myocardium.

T helper type 17 cells in immune-mediated glomerular disease.

CD4+ T cells are important drivers of tissue damage in immune-mediated renal diseases, such as anti-glomerular basement membrane glomerulonephritis, anti-neutrophil cytoplasmic antibody-associated glomerulonephritis, and lupus nephritis. The discovery of a distinct, IL-17-producing CD4+ T-cell lineage termed T helper type 17 (TH17) cells has markedly advanced current understanding of the pathogenic mechanisms of organ-specific immunity and the pathways that lead to target organ damage. TH17 cells are characterized by the expression of the transcription factor RORγt, the production of the pro-inflammatory cytokines IL-17A, IL-17F, IL-22, and high expression of the chemokine receptor C-C-motif chemokine receptor 6 (CCR6). An emerging body of evidence from experimental models and human studies supports a key role for these cells in the development of renal damage, and has led to the identification of targets to inhibit the production of TH17 cells in the intestine, their migration, or their actions within the kidney. Here, we describe the identification, regulation, and function of TH17 cells and their associated pathways in immune-mediated kidney diseases, with a particular focus on the mechanisms underlying renal tissue injury. We also discuss the rationale for the translation of these findings into new therapeutic approaches in patients with autoimmune kidney disease.

Interleukin-17F expression is elevated in hepatitis C patients with fibrosis and hepatocellular carcinoma

BackgroundThe role of interleukin (IL) 17A in chronic liver diseases had been extensively studied, but the function of IL-17F, which shares a high degree of homology with IL-17A, in the progression of chronic hepatic diseases is poorly understood. The aim of the study was to evaluate the association between IL-17F and liver diseases including, fibrosis and hepatocellular carcinoma (HCC).MethodsHepatic tumor samples from both hepatitis C virus (HCV) positive and negative patients (without HBV and HCV, NBNC) were examined with quantitative PCR and immunohistochemistry staining for inflammatory cytokine genes expression. In addition, 250 HCV patients naïve for interferon treatment were also subjected to enzyme-linked immunosorbent Assay (ELISA) for their serum cytokine concentrations.ResultsSerum IL-17F concentrations were significantly elevated in HCV patients with severe fibrosis stages. In accordance with serum data, IL-17F expression was also found higher in HCV-associated HCC tissues compared with NBNC HCC tissues at both the mRNA and protein levels.ConclusionsOur data suggest that IL-17F might be used as a valuable biological marker than IL-17A during chronic fibrosis progression and HCC development in HCV patients.

Herbal medicine Yinchenhaotang protects against \u03b1-naphthylisothiocyanate-induced cholestasis in rats

Cholestasis is a clinical disorder defined as an impairment of bile flow, and that leads to toxic bile acid (BA) accumulation in hepatocytes. Here, we investigated the hepatoprotective effect of Yinchenhaotang (YCHT), a well-known formulae for the treatment of jaundice and liver disorders, against the cholestasis using the α-naphthylisothiocyanate (ANIT)-induced cholestasis in male Wistar rats. ANIT feeding induced significant cholestasis with substantially increased intrahepatic retention of hydrophobic BAs. The dynamic changes of serum and liver BAs indicated that YCHT was able to attenuate ANIT-induced BA perturbation, which is consistent with the histopathological findings that YCHT significantly decreased the liver damage. YCHT treatment substantially reduced serum alanine aminotransferase (ALT), alkaline phosphatase (AST), total bilirubin (TBIL) and direct bilirubin (DBIL) with minimal bile duct damage in the ANIT treated rats. Elevated mRNA expression of liver IL-6, IL-17A, IL-17F, TGF-β1, α-SMA, TGR5, NTCP, OATP1a1, and ileum ASBT and decreased liver IL-10, FXR, CAR, VDR, BSEP, MRP2, MRP3, MRP4 was also observed in ANIT-induced cholestasis but were attenuated or normalized by YCHT. Our results demonstrated that the BA profiles were significantly altered with ANIT intervention and YCHT possesses the hepatoprotective potential against cholestatic liver injury induced by hepatotoxin such as ANIT.

Expression of mRNA IL-17F and sIL-17F in atopic asthma patients

BackgroundAsthma is a chronic inflammatory disorder of airway that involves many cells and elements. Chronic inflammation caused by increase Airway hyperresponsiveness that cause recurrent episodic symptoms of breathlessness, wheezing, chest tightness and coughing, especially at night or early morning. Interleukin 17F is a cytokine that plays an important role in the pathophysiology of asthma attacks. Some studies show a variety of IL-17F roles in the pathogenesis of airway inflammation due to an allergic reaction.ResultsThe study was conducted at the Prof. Dr. R. D. Kandou Manado Hospital, Indonesia. Samples were taken continuously until the number of meant samples was achieved. Blood samples were collected from 40 atopic asthmatic patients. From statistical analysis based on the hypothesis, there was positive correlation between mRNA levels of IL-17F and IL-17F in atopic asthmatic patient (p = 0.000 and r = 0.988).ConclusionsAccording these data suggest that levels of mRNA IL-17F and IL17F might be useful parameters for the diagnosis of atopic asthma patient.

Expression, Regulation, and Effects of Interleukin-17f in the Human Ocular Surface

ABSTRACTPurpose: To evaluate the basal and possibly stimulated expression of interleukin (IL)-17 in the context of the ocular surface and potential downstream effects.Methods: Western blot and immunofluorescent staining were used to evaluate IL-17F expression in human cornea/conjunctival tissues and cornea epithelial cell line. Cytokines and matrix metalloproteinase (MMP) transcripts were quantified by qPCR. IL-17F effects on NF-κB were investigated by the secretary alkaline phosphatase assay.Results: IL-17F was expressed in the cytoplasm of human corneal and conjunctival epithelial tissues. In the corneal cell line, exogenous IL-17F did not increase the NF-κB activity, but Pam3CSK4 increased IL-17F transcripts. IL-17F stimulated MMP-9 activity, promoted IL-6, IL-8, tumor necrosis factor-α transcripts levels, and depressed monocyte chemoattractant protein-1 expression, but did not affect transforming growth factor beta-1 transcript levels.Conclusions: Normal corneal/conjunctival epithelial cells express IL-17F. Microbial agents may stimulate IL-17F via the NF-κB pathway. Matrix dissolution stimulated by IL-17F may have a role in the melting and necrosis of cornea in severe inflammation.

The effects of direct-fed microbial supplementation, as an alternative to antibiotics, on growth performance, intestinal immune status and epithelial barrier protein expression in broiler chickens

Abstract This study was conducted to investigate the effects of Bacillus subtilis supplementation in broiler chicken diets on growth performance, feed efficiency, intestinal cytokine and tight junction (TJ) protein mRNA expression. Day-old broiler chicks (n = 140) were to one of five dietary treatments: basal diet (CON), basal diet supplemented with antibiotic (BMD) or probiotics, namely B. subtilis strain 1781 (PB1), a combination of B. subtilis strain 1104+strain 747 (PB2) or B. subtilis strain 1781+strain 747 (PB3). At 14 days of age, ileal samples were collected and used for intestinal cytokine, TJ protein and mucin gene expression analysis using qRT-PCR. The chickens fed with antibiotic (BMD) and B. subtilis strain 1781 alone (PB1) had significantly higher body weights compared to controls of the same age. Dietary supplementation with antibiotic (BMD) or probiotics (PB1, PB2, PB3) significantly improved the feed efficiency as evidenced by decreased FCR compared to controls. No differences were observed in the expression of IL1β, IL17F, IFNγ and MUC2 gene among the different treatment groups. However, elevated expression of IL6 (BMD, PB1, PB2), IL8 (PB2) and TNFSF15 (PB1, PB2, PB3) compared to controls was observed in the ileum. IL2 and IL10 expression was upregulated in chicks in the PB2 and PB3 groups, and IL4 was elevated in the PB1 group. IL13 was elevated in all probiotic-fed groups. Probiotic supplementation was also shown to significantly increase the expression of TJ proteins JAM2, ZO1 (PB2, PB3) and occludin (PB1, PB2). Taken together, B. subtilis supplementation altered intestinal immune activity and influenced gut barrier integrity through increased expression of TJ proteins.

The Effects of Direct-fed Microbial Supplementation, as an Alternative to Antibiotics, on Growth Performance, Intestinal Immune Status, and Epithelial Barrier Gene Expression in Broiler Chickens

The objective of this study was to investigate the effects of Bacillus subtilis-based probiotic supplementation in broiler chicken diets on growth performance, feed efficiency, intestinal cytokine, and tight junction (TJ) protein mRNA expression. Zero-day-old broiler chicks (n=140) were randomly assigned to one of five dietary treatments: basal diet (CON); basal diet supplemented with either antibiotic bacitracin methylene disalicylate (BMD); or probiotics, namely, B. subtilis strain 1781 (PB1), a combination of B. subtilis strain 1104+strain 747 (PB2), or B. subtilis strain 1781+strain 747 (PB3). Body weight and feed intake were measured at 14days of age, and the feed conversion ratio (FCR) was calculated. At 14days of age, ileal samples were collected and used for intestinal cytokine, TJ protein, and mucin gene expression analysis using qRT-PCR. The chickens supplemented with antibiotic (BMD) and B. subtilis strain 1781 alone (PB1) had significantly higher body weights compared to controls of the same age. Dietary supplementation with antibiotic (BMD) or probiotics (PB1, PB2, PB3) significantly improved the feed efficiency as evidenced by decreased FCR compared to controls. No differences were observed in the expression of IL1β, IL17F, IFNγ, and MUC2 gene among the different treatment groups. However, elevated expression of IL6 (BMD, PB1, PB2), IL8 (PB2), and TNFSF15 (PB1, PB2, PB3) compared to controls was observed in the ileum. IL2 and IL10 expression was upregulated in chicks in the PB2 and PB3 groups, and IL4 was elevated in the PB1 group. IL13 was elevated in all probiotic-fed groups (PB1, PB2, PB3). Probiotic supplementation was also shown to significantly increase the expression of TJ proteins JAM2, ZO1 (PB2, PB3), and occludin (PB1, PB2). Taken together, B. subtilis supplementation altered intestinal immune activity and influenced gut barrier integrity through increased tight junction gene expression.

IL-17F regulates psoriasis-associated genes through IκBζ.

Psoriasis is a common chronic inflammatory and immune-mediated skin disease. Antagonists of TNF-α and, recently, IL-17 have proven to be highly effective in the treatment for psoriasis; however, the molecular mechanisms involved in the pathogenesis of psoriasis are poorly understood. Recently, we presented evidence that IκBζ is a key regulator in the development of psoriasis through its role in mediating IL-17A-driven effects. Like IL-17A, IL-17F is produced by a variety of immune cells, and the expression of IL-17F is increased in psoriatic skin. The purpose of this study was to characterize the role of IL-17F in the regulation of IκBζ expression and to investigate whether IL-17F regulates psoriasis-associated genes in human keratinocytes through IκBζ. Here, we demonstrate that IL-17F stimulation induces IκBζ expression at both the mRNA and the protein levels in normal human keratinocytes. Moreover, silencing IκBζ by siRNA revealed that IκBζ is a key regulator of specific IL-17F-inducible psoriasis-associated genes and proteins, including DEFB4/hBD2, S100A7, CCL20, IL-8 and CHI3L1. In addition, IL-17F-induced IκBζ expression is mediated by a mechanism involving the p38 MAPK and NF-κB signalling pathways, as shown by the clear reduction in IL-17F-mediated expression of IκBζ during chemical inhibition of these two signalling pathways. In summary, we present IκBζ as a novel key regulator of IL-17F-driven effects in psoriasis. Thus, antagonists to IκBζ could potentially provide a more targeted approach for treating psoriasis as well as for treating the other inflammatory and immune-mediated diseases for which IL-17-targeting drugs have recently been approved.

Madecassic acid, the contributor to the anti-colitis effect of madecassoside, enhances the shift of Th17 toward Treg cells via the PPAR\u03b3/AMPK/ACC1 pathway

The imbalance between Th17 and Treg cells substantially contributes to the intestinal immune disturbance and subsequent tissue injury in ulcerative colitis. The triterpenoid-rich fraction of Centella asiatica was able to ameliorate dextran sulfate sodium-induced colitis in mice. Here we explored its active ingredient and underlying mechanism with a focus on restoring the Th17/Treg balance. The four main triterpenoids occurring in C. asiatica were shown to attenuate colitis in mice by oral administration. The most effective ingredient madecassoside lost anti-colitis effect when applied topically in the colon, and madecassic acid was recognized to be the active form of madecassoside. Oral administration of madecassic acid decreased the percentage of Th17 cells and downregulated the expression of RORγt, IL-17A, IL-17F, IL-21 and IL-22 and increased the percentage of Treg cells and the expression of Foxp3 and IL-10 in the colons of mice with colitis, but it did not affect Th1 and Th2 cells. Under Th17-polarizing conditions, madecassic acid downregulated ACC1 expression and enhanced the shift of Th17 cells toward Treg cells, but it did not affect the differentiation of Treg cells under Treg-polarizing conditions. Both compound C and AMPK siRNA inhibited the madecassic acid-mediated downregulation of ACC1 expression and shift of Th17 cells to Treg cells under Th17-polarizing conditions. GW9662, T0070907 and PPARγ siRNA blocked the effect of madecassic acid on AMPK activation, ACC1 expression and shift of Th17 cells to Treg cells. Furthermore, madecassic acid was identified as a PPARγ agonist, as it promoted PPARγ transactivation. The correlation between activation of PPARγ and AMPK, downregulation of ACC1 expression, restoration of Th17/Treg balance and attenuation of colitis by madecassic acid was validated in mice with DSS-induced colitis. In conclusion, madecassic acid was the active form of madecassoside in ameliorating colitis by restoring the Th17/Treg balance via regulating the PPARγ/AMPK/ACC1 pathway.

Abnormal CD161+ immune cells and retinoic acid receptor–related orphan receptor γt–mediate enhanced IL-17F expression in the setting of genetic hypertension

Hypertension is considered an immunologic disorder. However, the role of the IL-17 family in genetic hypertension in the spontaneously hypertensive rat (SHR) has not been investigated. We tested the hypothesis that enhanced TH17 programming and IL-17 expression in abundant CD161+ immune cells in SHRs represent an abnormal proinflammatory adaptive immune response. Furthermore, we propose that this response is driven by the master regulator retinoic acid receptor-related orphan receptor γt (RORγt) and a nicotinic proinflammatory innate immune response. We measured expression of the CD161 surface marker on splenocytes in SHRs and normotensive control Wistar-Kyoto (WKY) rats from birth to adulthood. We compared expression of IL-17A and IL-17F in splenic cells under different conditions. We then determined the functional effect of these cytokines on vascular reactivity. Finally, we tested whether pharmacologic inhibition of RORγt can attenuate hypertension in SHRs. SHRs exhibited an abnormally large population of CD161+ cells at birth that increased with age, reaching more than 30% of the splenocyte population at 38weeks. The SHR splenocytes constitutively expressed more RORγt than those of WKY rats and produced more IL-17F on induction. Exposure of WKY rat aortas to IL-17F impaired endothelium-dependent vascular relaxation, whereas IL-17A did not. Moreover, invivo inhibition of RORγt by digoxin decreased systolic blood pressure in SHRs. SHRs have a markedly enhanced potential for RORγt-driven expression of proinflammatory and prohypertensive IL-17F in response to innate immune activation. Increased RORγt and IL-17F levels contribute to SHR hypertension and might be therapeutic targets.

Evaluation of IL-17B and IL-17F mRNA expression in peripheral blood mononuclear cells and association with clinical outcome of IBD patients.

In this study, we determined the gene expression analysis of IL-17 gene family for early detection of subclinical inflammation among IBD patients. Cytokines have a vital role in the pathogenesis of inflammatory bowel disease (IBD). Interleukin-17 is the signature cytokine of the recently identified T helper 17 (Th17) cell subset. IL-17F is mainly involved in mucosal host defense mechanisms whereas the functions of IL-17B remain largely elusive. In this cross-sectional study, IBD patients divided into two active and inactive groups. Peripheral blood mononuclear cells (PBMCs) from 38 IBD patients which 20 inactive samples and 18 active individuals were collected. Changes of IL-17 F and IL-17B mRNA expression level evaluated by quantitative-real time-PCR. mRNA expression level of IL-17B and IL-17F in CD, UC, active and inactive groups have been assessed and there were no significant differences (P>0.05). Patients were classified into five different categories as follows: i) 5ASA; ii) 5ASA + Pred; iii) 5ASA + AZA; iv) 5ASA + Pred + AZA; v) 5ASA + Pred + AZA + IFX according to medication usage, expression of IL-17F and IL-17B had no differences (p>0.05). Evaluation of IL-17B and IL-17F mRNA expression level illustrate no difference among active and inactive patients. Therefore, IL-17B and IL-17F are not biomarkers in an Iranian IBD patients.

Association of IL-17A/F polymorphisms with the risk of gastritis and gastric cancer in the Korean population

We investigated the effects of IL-17A rs2275913 and IL-17F rs763780 polymorphisms on IL-17 expression and the association of these polymorphisms with the risk of gastritis and gastric cancer. IL-17A expression was closely associated with the degree of gastritis in 55 non-neoplastic gastric mucosae and was markedly decreased in subjects carrying A allele. In addition, IL-17F expression was increased in the T allele carriers, but was not associated with gastritis. In 300 gastric cancer patients, the frequency of the rs2275913 A/A genotype was significantly higher in intestinal-type gastric cancer, when compared to that of diffuse-type gastric cancer (P>0.05). There was a significant difference in genotype distribution and allele frequencies of IL-17F rs763780 when comparing gastric cancer patients and 247 healthy controls. These results suggest that the polymorphisms of IL-17F rs763780 and IL-17A rs2275913 are closely associated with susceptibility to the development of gastritis and gastric cancer in the Korean population.

346 IL-17F regulates psoriasis-associated genes through IκBζ

Psoriasis is a common chronic inflammatory and immune-mediated skin disease. Antagonists of TNFα and, recently, IL-17 have proven to be highly effective in the treatment of psoriasis; however, the molecular mechanisms involved in the pathogenesis of psoriasis are poorly understood. Recently, we presented evidence that the nuclear localized protein IκBζ is a key regulator in the development of psoriasis through its role in mediating IL-17A-driven effects. Like IL-17A, IL-17F is produced by a variety of immune cells, and the expression of IL-17F is augmented in psoriatic skin. The aim of this study was to characterize the role of IL-17F in the regulation of IκBζ expression. Here, we demonstrate that IL-17F stimulation increases IκBζ expression at both the mRNA and the protein levels in cultured normal human keratinocytes. Moreover, gene silencing of IκBζ by siRNA revealed that IκBζ is a key regulator of specific IL-17F-inducible psoriasis-associated genes and proteins, including DEFB4/hBD2, S100A7, CCL20, IL-8 and CHI3L1. In addition, IL-17F-induced IκBζ expression is mediated by a mechanism, which involve the p38 MAPK and NF-κB signalling pathways, as shown by a clear reduction in IL-17F-mediated expression of IκBζ during chemical inhibition of these two signalling pathways. In summary, we present IκBζ as a novel key regulator of IL-17F-driven effects in psoriasis. Thus, antagonists to IκBζ could potentially provide a more targeted approach for treating psoriasis as well as for treating other inflammatory and immune-mediated diseases for which IL-17-targeting drugs have recently been approved.

Abstract 1420: IL17F-rs9463772 independently predicts long-term outcome in locally advanced rectal cancer

Abstract Host genetic variation in the immune factors has the potential to highlight individual characteristics of tumor risk, prognosis, and response to treatment. In locally advanced rectal cancer (LARC) no predictive and prognostic factors are available to select patients for multimodality treatment comprising neoadjuvant chemoradiation followed by radical surgery, and possibly adjuvant chemotherapy. This work aimed at identifying immunogenetic markers of prognostic significance in LARC patients treated by multimodality treatment. A panel of 192 tagging polymorphisms (SNPs) in 34 immuno-system related genes was selected and analyzed in a Veracode (Illumina) platform on 250 LARC patients (training set) treated with neo-adjuvant therapy, and followed up for at least 24 months after radical surgery. The primary clinical end-point of the study was 2-years recurrence status which has been reported to be the most reliable long-term prognostic factor in these patients. Significant SNPs were then tested on 10-years overall survival (OS). An independent validation set comprising of 63 rectal cancer patients was used to replicate the results. Training set analysis identified 4 markers significantly associated with 2-years recurrence status by multivariate logistic regression which were still significant after bootstrap validation, according to a dominant genetic model: three of them were risk factors, IL17F-rs641701 (P = 0.002), IL17F-rs9463772 (P = 0.009), TGF-beta- rs9867701 (P = 0.020); one of them was a protective factor, STAT3-rs8069645 (P = 0.025). Three of them were also associated to 10-years OS by multivariate COX regression: IL17F-rs641701 (P = 0.003); IL17F-rs9463772 (P = 0.002) were risk factors for death; STAT3-rs8069645 (P = 0.003) was a protective factor. The prognostic effect of IL17F-rs9463772 on 10-years OS was replicated using the validation set (P = 0.045). IL17F is a cytokine with onco-suppressing and anti-angiogenic effects, previously reported to be down-regulated in colorectal tumor as compared to healthy tissue. Although no functional data are available for the intronic rs9463772, it might be involved in the regulation of IL17F expression level affecting tumor prognosis. In conclusion IL17F-rs9463772 represents a validated prognostic marker of long term survival in LARC patients, further studies are warranted to provide functional evidence to support these findings. Citation Format: Cecchin Erika, Eva Dreussi, Sara Gagno, Chiara Zanusso, Marcella Montico, Claudio Belluco, Antonino De Paoli, Salvatore Pucciarelli, Luca Quartuccio, Salvatore De Vita, Vincenzo Canzonieri, Angela Buonadonna, Maria Luisa Friso, Sara Lonardi, Giuseppe Toffoli. IL17F-rs9463772 independently predicts long-term outcome in locally advanced rectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1420.

Erratum to: "Increased IL-17A/IL-17F expression ratio represents the key mucosal T helper/regulatory cell-related gene signature paralleling disease activity in ulcerative colitis".

Background T helper (Th) and regulatory T (Treg) cell-related cytokines are implicated in inflammatory bowel diseases, including ulcerative colitis (UC). While these cytokines are generally upregulated in inflamed mucosae, the key cytokine profile explaining disease severity has not been determined.

Increased IL-17A/IL-17F expression ratio represents the key mucosal T helper/regulatory cell-related gene signature paralleling disease activity in ulcerative colitis.

T helper (Th) and regulatory T (Treg) cell-related cytokines are implicated in inflammatory bowel diseases, including ulcerative colitis (UC). While these cytokines are generally upregulated in inflamed mucosae, the key cytokine profile explaining disease severity has not been determined. The Rachmilewitz endoscopic index (REI) was assessed in 61 UC patients undergoing colonoscopy. Biopsies obtained from inflamed (REI 3-12) and noninflamed (REI 0-2) areas were analyzed by quantitative PCR for expression of mRNAs encoding cytokines and transcription factors related to Th1 (TNF-α, IFN-γ, IL-12p35, IL-12p40, and T-bet), Th2 (IL-4, IL-13, IL-33, and GATA3), Th17 (IL-17A, IL-17F, IL-21, IL-22, IL-23p19,IL-6, and RORC), Th9 (IL-9, IRF4, and PU.1), and Treg (TGF-β and Foxp3). Expression patterns associated with higher REI were determined by univariate and multivariate analyses. Despite general upregulation, none of these mRNAs showed univariate correlation with REI in inflamed samples. Multiple regression analysis, however, found that joint expression of IL-17A, IL-17F, IL-21, RORC, and TGF-β was significantly predictive of REI (P<0.0002, R2=0.380), with major individual contributions by IL-17A (P<0.0001) and IL-17F (P<0.0001), which were associated with increased and decreased REI, respectively. Partial correlation analysis, validating this model, indicated differences between IL-17A and IL-17F in correlating with other targets. The IL-17A/IL-17F ratio showed a significant correlation with REI (r=0.5124, P<0.0001), whereas no other mRNAs were essentially predictive of REI. Mucosal IL-17A/IL-17F ratio significantly correlates with endoscopic score in UC patients, accompanied by their disparate interactions with other Th/Treg-related genes.