Expression Of IL-17C Research Articles

Genome-wide DNA methylation mediates the resistance to vibriosis in Cynoglossus semilaevis

Chinese tongue sole (Cynoglossus semilaevis) is an economically important marine fish in China. However, vibriosis has caused huge mortality and economic losses in its culturing industry. To reveal the effect of DNA methylation on the resistance to vibriosis in tongue sole, we conducted RNA sequencing and whole genome bisulfite sequencing (WGBS), and compared the gene expressions and DNA methylation patterns between the resistant and susceptible families. We identified a total of 741 significantly differentially expressed genes (DEGs) in kidney and 17460 differentially methylated genes (DMGs), which were both enriched in immune-related pathways, such as “cAMP signaling pathway” and “NOD-like receptor signaling pathway”. Through the correlation analysis of DEGs and DMGs, we identified two important immune pathways, including “complement and coagulation cascades”, and “cytokine-cytokine receptor interaction”, which played important roles in regulating the inflammation level and immune homeostasis. For example, the expression of proinflammatory cytokine il17c was down-regulated under the regulation of DNA methylation; in addition, the expression of protease-activated receptor 3 (par3) was up-regulated, which could induce the up-expressionof il8. These results demonstrated that the regulation of DNA methylation on the genes involved in immune responses might contribute to the resistance to vibriosis in tongue sole, and provided a basis for the control of diseases in fish aquaculture.

Aldehyde Dehydrogenase 2 Protects the Kidney from Ischemia-Reperfusion Injury by Suppressing the IκBα/NF-κB/IL-17C Pathway.

Ischemia-reperfusion injury (IRI) is an important cause of delayed functional recovery after transplantation. This study is aimed at investigating the molecular mechanism of ALDH2 in a kidney ischemia-reperfusion model based on RNA-seq. We performed kidney ischemia-reperfusion in ALDH2-/- and WT mice and evaluated kidney function and morphology using SCr, HE staining, TUNEL staining, and TEM. We used RNA-seq to compare mRNA expression in ALDH2-/- and WT mice after IR, and then, we verified the related molecular pathways by PCR and western blotting. In addition, activators and inhibitors of ALDH2 were used to alter the activity of ALDH2. Finally, we established a model of hypoxia and reoxygenation in HK-2 cells and clarified the role of ALDH2 in IR by interfering with ALDH2 and using an NF-κB inhibitor. After kidney ischemia-reperfusion, the SCr value increased significantly, kidney tubular epithelial cells were damaged, and the apoptosis rate increased. In the microstructure, mitochondria were swollen and deformed, and ALDH2 deficiency aggravated these changes. The NF-κB pathway and IL-17 pathway were significantly enriched in ALDH2-/- mice compared with WT mice according to KEGG enrichment analysis of the RNA-seq data. The PCR results showed that the mRNA expression levels of IκBα and IL-17B, C, D, E, and F were significantly higher than those in the WT-IR group. Western blot verification results showed that ALHD2 knockdown resulted in increased phosphorylation of IκBα, increased phosphorylation of NF-κB, and increased expression of IL-17C. When we used ALDH2 agonists, the number of lesions and the expression levels of the corresponding proteins were reduced. Knockdown of ALDH2 in HK-2 cells resulted in a higher proportion of apoptotic cells after hypoxia and reoxygenation, but inhibiting the phosphorylation of NF-κB prevented the increase in apoptosis and reduced the protein expression level of IL-17C. ALDH2 deficiency can lead to the aggravation of kidney ischemia-reperfusion injury. RNA-seq analysis and validation by PCR and western blotting revealed that this effect may be due to the promotion of IκBα/NF-κB p65 phosphorylation during ischemia-reperfusion caused by ALDH2 deficiency, which then leads to an increase in inflammatory factors, including IL-17C. Thus, cell death is promoted, and kidney IRI is eventually aggravated. We link ALDH2 deficiency with inflammation, revealing a new idea for ALDH2-related research.

Ceramide Analysis in Combination With Genetic Testing May Provide a Precise Diagnosis for Self-Healing Collodion Babies

Self-healing collodion baby (SHCB), also called “self-improving collodion baby”, is a rare mild variant of autosomal recessive congenital ichthyosis and is defined as a collodion baby who shows the nearly complete resolution of scaling within the first 3 months to 1 year of life. However, during the neonatal period, it is not easy to distinguish SHCB from other inflammatory forms of autosomal recessive congenital ichthyosis, such as congenital ichthyosiform erythroderma. Here, we report a case study of two Japanese SHCB patients with compound heterozygous mutations, c.235G>T (p.(Glu79∗))/ c.1189C>T (p.(Arg397Cys)) and c.1295A>G (p.(Tyr432Cys))/ c.1138delG (p.(Asp380Thrfs∗3)), in CYP4F22, which encodes cytochrome P450, family 4, subfamily F, polypeptide 22 (CYP4F22). Immunohistochemically, inflammation with the strong expression of IL-17C, IL-36γ, and TNF-α was seen in the skin at birth. CYP4F22 is an ultra-long-chain FA ω-hydroxylase responsible for ω-O-acylceramide (acylceramide) production. Among the epidermal ceramides, acylceramide is a key lipid in maintaining the epidermal permeability barrier function. We found that the levels of ceramides with ω-hydroxy FAs including acylceramides and the levels of protein-bound ceramides were much lower in stratum corneum samples obtained by tape stripping from SHCB patients than in those from their unaffected parents and individuals without SHCB. Additionally, our cell-based enzyme assay revealed that two mutants, p.(Glu79∗) and p.(Arg397Cys), had no enzyme activity. Our findings suggest that genetic testing coupled with noninvasive ceramide analyses using tape-stripped stratum corneum samples might be useful for the early and precise diagnosis of congenital ichthyoses, including SHCB.

Th17-Derived Cytokines Synergistically Enhance IL-17C Production by the Colonic Epithelium.

Tightly regulated communication between the gastrointestinal epithelium and immune cells in the underlying lamina propria is critical for immune homeostasis and inflammation. IL-17C, produced by epithelial cells after exposure to inflammatory stimuli, facilitates cell-to-cell communication by promoting inflammatory responses in Th17 cells. In this study, we demonstrate that Th17-derived cytokines TNF-α, IL-17A, and IL-22 synergistically enhance IL-17C expression in both human-transformed colonic epithelial cell lines and primary non-inflammatory bowel disease colonic epithelial spheroids. This synergistic expression requires activation of the transcription factor NF-κB downstream of the TNF-α stimulus, evidenced by the reduction of IL-17C expression in the presence of an IκBα inhibitor. IL-17A and IL-22 enhance IL-17C expression through the activation of the transcription factor AP-1 in a p38 MAPK-dependent manner. Colonic spheroids derived from uninvolved epithelial of ulcerative colitis patients stimulated with TNF-α, IL-17A, and IL-22 show muted responses compared with non-inflammatory bowel disease spheroids, and inflamed spheroids yielded more IL-17C expression in the presence of TNF-α, and no response to IL-22 stimulation. Altogether, a role for IL-17C in activating Th17 cells combined with our findings of Th17-derived cytokine-driven synergy in the expression of IL-17C identifies a novel inflammatory amplification loop in the gastrointestinal tract between epithelial cells and Th17 cells.

Oxidative stress and expression of inflammatory factors in lung tissue of acute mountain sickness rats.

The aim of the present study was to investigate the changes in lung histomorphology and oxidative stress, as well as the expression of interleukin (IL)-17C and other inflammatory factors during acute mountain sickness (AMS) in male Sprague-Dawley rats and to explore the underlying mechanism. Rats were randomly divided into a control group (0 h) and three hypoxia stress groups, exposed to low-pressure oxygen storage at a simulated altitude of 6,000 m for 24, 48 and 72 h, respectively. Morphological changes in lung tissue were observed by hematoxylin and eosin staining under light microscopy and transmission electron microscopy. The expression of inflammatory factors IL-17C, nuclear factor-κB (NF-κB), IL-1β, IL-6 and tumor necrosis factor-α (TNF-α) in lung tissue was assessed by RNA sequencing and verified by reverse transcription-quantitative PCR (RT-qPCR) and western blotting (WB). Superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) enzyme activity and malondialdehyde (MDA) expression were also measured. Experimental groups were compared to the control group following 24, 48 and 72 h of hypoxic stress. Lung tissue suffered from different degrees of injury, and the damage was the most severe after 48 h of hypoxic stress. RNA sequencing data from the lung tissue of rats from each group suggested that the expression of IL-17C, NF-κB, IL-1β, IL-6, and TNF-α increased significantly after hypoxic stress. RT-qPCR and WB demonstrated that the expression of IL-17C and NF-κB increased significantly after hypoxia lasting 48 and 72 h. IL-1β expression increased significantly after hypoxia stress lasting 24 and 48 h, and the expressions of TNF-α and IL-6 increased significantly after hypoxia stress lasting 24, 48 and 72 h (P<0.01). The enzyme activity of SOD and GSH-Px decreased significantly after lasting 24, 48 and 72 h of hypoxia (P<0.01), and MDA increased significantly after hypoxic stress lasting 48 and 72 h (P<0.01). In conclusion, under hypoxic stress, rats quickly initiate oxidative stress and immune responses. However, with prolonged hypoxic stress time, excessive oxidative stress can further stimulate the immune system in vivo, and release a large quantity of inflammatory factors accumulating in the body. This, in turn, may lead to the occurrence of inflammatory storms and further damage the lung tissue resulting in AMS.

Genome-wide identification of interleukin-17 (IL-17) / interleukin-17 receptor (IL- 17R) in turbot (Scophthalmus maximus) and expression pattern analysis after Vibrio anguillarum infection

Interleukin-17 (IL-17) is a cytokine secreted by a variety of immune cells that plays an important role in host defense against pathogens. IL-17 usually activates downstream immune signaling pathway by binding to heterodimeric or homodimeric complex formed by IL-17 receptors (IL-17R). Describing the characteristics, tissue distribution of IL-17 and IL-17 receptor family members and their expression after pathogen infection will provide a reference for host defense against disease of turbot. In this study, six IL-17 family members and nine IL-17 receptor family members were identified by analyzing the turbot (Scophthalmus maximus) genome. Different from other vertebrates, most members of the IL-17 receptor family own two copies. Protein structure analysis showed that the six IL-17 family members contained typical “IL-17” domains, and the nine IL-17 receptor family members contained typical “SEFIR domain” or “IL17_R_N domain”. Syntenic analysis revealed that all IL-17s and IL-17Rs were chromosomally conserved compared with other fish. The phylogenetic analysis further confirmed the evolutionary conservatism of different copies of IL-17C and IL-17Rs. Tissue distribution results showed that IL-17 and IL-17R genes were highly expressed in immune-related tissues. The expression of IL-17C and its receptor in the mucosal immune tissues after infection with V. anguillarum were analyzed subsequently, which were significantly increased in the skin. The results are consistent with previous studies showing that IL-17 and IL-17 receptor play an important role in promoting innate immune response.

Epicutaneous challenge with protease allergen requires its protease activity to recall TH2 and TH17/TH22 responses in mice pre-sensitized via distant skin

Epicutaneous exposure to allergenic proteins is an important sensitization route for skin diseases like protein contact dermatitis, immunologic contact urticaria, and atopic dermatitis. Environmental allergen sources such as house dust mites contain proteases, which are frequent allergens themselves. Here, the dependency of T-helper (TH) cell recall responses on allergen protease activity in the elicitation phase in mice pre-sensitized via distant skin was investigated. Repeated epicutaneous administration of a model protease allergen, i.e. papain, to the back skin of hairless mice induced skin inflammation, serum papain-specific IgE and TH2 and TH17 cytokine responses in the sensitization sites, and antigen-restimulated draining lymph node cells. In the papain-sensitized but not vehicle-treated mice, subsequent single challenge on the ear skin with papain, but not with protease inhibitor-treated papain, up-regulated the gene expression of TH2 and TH17/TH22 cytokines along with cytokines promoting these TH cytokine responses (TSLP, IL-33, IL-17C, and IL-23p19). Up-regulation of IL-17A gene expression and cells expressing RORγt occurred in the ear skin of the presensitized mice even before the challenge. In a reconstructed epidermal model with a three-dimensional culture of human keratinocytes, papain but not protease inhibitor-treated papain exhibited increasing transdermal permeability and stimulating the gene expression of TSLP, IL-17C, and IL-23p19. This study demonstrated that allergen protease activity contributed to the onset of cutaneous TH2 and TH17/TH22 recall responses on allergen re-encounter at sites distant from the original epicutaneous sensitization exposures. This finding suggested the contribution of protease-dependent barrier disruption and induction of keratinocyte-derived cytokines to the recall responses.

An integrated network pharmacology and RNA-Seq approach for exploring the preventive effect of Lonicerae japonicae flos on LPS-induced acute lung injury

Ethnopharmacological relevanceLonicerae japonicae flos (LJF, the dried flower bud or newly bloomed flower of Lonicera japonica Thunb.), a typical herbal medicine, targets the lung, heart and stomach meridian with the function of clearing heat and detoxication. It ameliorated inflammatory responses and protected against acute lung inflammation in animal models. Acute lung injury (ALI) is a kind of inflammatory disease in which alveolar cells are damaged. However, a network pharmacology study to thoroughly investigate the mechanisms preventing ALI has not been performed. Aim of the studyIn this study, we examined the main active ingredients in LJF and the protective effects of LJF on LPS-induced ALI in rats. Materials and methodsFirst, the main active ingredients of LJF were screened in the TCMSP database, and the ALI-associated targets were collected from the GeneCards database. Then, we used compound-target and target-pathway networks to uncover the preventive mechanisms of LJF. Furthermore, we assessed the preventive effects of LJF in an LPS-induced rat model with the RNA-Seq technique to validate the possible molecular mechanisms of the effects of LJF in the treatment of ALI. ResultsThe network pharmacology results identified 28 main active compounds in LJF, and eight chemical components highly related to the potential targets, which were potential active compounds in LJF. In all, 94 potential targets were recognized, including IL6, TNF, PTGS2, APP, F2, and GRM5. The pathways revealed that the possible targets of LJF involved in the regulation of the IL-17 signalling pathway. Then, in vivo experiments indicated that LJF decreased the levels of proinflammatory cytokines (TNF-, IL-1, and IL-6) in serum and bronchoalveolar lavage fluid, decreased the levels of oxidative stress factors (MDA and MPO) and increased the activities of SOD and GSH-Px in lung tissue. The RNA-Seq results revealed that 7811, 775 and 3654 differentially expressed genes (DEGs) in Ctrl (control group), ALI-LJF (Lonicerae japonicae flos group) and ALI-DXSM (dexamethasone group), respectively. KEGG pathway analysis showed that the DEGs associated with immune response and inflammation signalling pathways and the IL-17 signalling pathway were significantly enriched in LJF. Compared with those in ALI, the expression of CXCL2, CXCL1, CXCL6, NFKBIA, IFNG, IL6, IL17A, IL17F, IL17C, MMP9 and TNFAIP3, which are involved in the IL-17 signalling pathway, were significantly decreased in the LJF group according to the qRT-PCR analyses. ConclusionsIn view of the network pharmacology and RNA-Seq results, the study identified the main active ingredient and potential targets of LJF involved in protecting against ALI, which suggests directions for further research on LJF.

Th17-derived cytokines synergistically enhance IL-17C production by the colonic epithelium

Abstract Tightly regulated communication between the gastrointestinal (GI) epithelium and immune cells in the underlying lamina propria is critical for immune homeostasis. Interleukin (IL)-17C, produced by epithelial cells after exposure to inflammatory stimuli, facilitates cell-to-cell communication by promoting pro-inflammatory responses in Th17 cells. Since Th17-derived cytokines induce the expression of IL-17C, we hypothesize that IL-17C participates in an inflammatory amplification loop with Th17-derived cytokines, contributing to GI disease. We report that a Th17-derived cytokine TNFα induces IL-17C mRNA and protein expression in human colonic epithelial cell lines via an NFκB dependent pathway. Co-stimulation of TNFα-treated cells with Th17-derived IL-17A or IL-22 induces a respective 2,000- and 1,000-fold increase in IL-17C mRNA and protein. All three cytokines stimulate an 11,000-fold increase of IL-17C. While neither IL-17A nor IL-22 alone induce IL-17C synthesis, their presence at culture initiation is necessary to achieve synergy, suggesting that they stimulate the cells independently from TNFα. Inhibition of NFκB activation reduces IL-17C production by 99.99%, confirming that TNFα is the primary stimulant. Inhibition of AP-1 reduces IL-17C mRNA synthesis induced by pairwise or triple cytokine exposure to levels equivalent to that of TNFα alone, suggesting a role for this transcription factor in the synergistic response. IL-17A-mediated RNA stability was shown not to contribute to the mechanism of synergy. Taken together, cooperation between the NFκB and AP-1 signaling pathways in colonic epithelial cells may mediate the synergy observed in this novel pro-inflammatory feed-forward loop in the GI tract.

Brodalumab: A new way to inhibit IL-17 in psoriasis.

Psoriasis is a chronic inflammatory disease that affects 2% to 4% of the population; about 20% of the patients present a moderate-to-severe form. The IL-23/Th17/IL-17 molecular axis is considered crucial in the pathogenesis of psoriasis and IL-17 is fundamental in the maintenance of the immune and inflammatory alterations causing psoriasis. Expression of IL-17A, IL-17F, and IL-17C is strongly increased in psoriatic plaques. Effective therapy leads to restoration of the expression of a wide range of genes (including effector cytokines and chemokines downstream of IL-17) to near normal levels. Brodalumab is the first biologic drug targeting specifically the subunit A of the IL-17 receptor (IL-17RA) and thus inhibiting not only IL-17A but also other members of the IL-17 family. Brodalumab is very effective and safe in treating moderate-to severe psoriasis.

IL-17C expression and its correlation with pediatric adenoids: a preliminary study.

Objective: Interleukin-17 (IL-17) C is a cytokine expressed by epithelial cells in response to bacterial stimulation. In contrast to other members of the IL-17 family of cytokines, IL-17C is upregulated early during infection, maintains integrity of the epithelial layer barrier, and mediates the innate immune response. We investigated the expression profile of IL-17C in pediatric adenoids.Methods: Pediatric adenoid tissues and lavage fluids were collected from a total of 38 subjects. The Limulus amebocyte lysate test and real-time PCR using Staphylococcus aureus primers were performed to evaluate bacterial contents in adenoids. Expression of IL-17RE in adenoids was analyzed using real-time polymerase chain reaction and western blot. The expression of IL-17C was evaluated by western blot and immunohistochemistry and compared between allergic rhinitis (AR) and control subjects. The levels of Hsp27, Hsp70, and IL-17C in adenoid lavage fluids were evaluated by enzyme-linked immunosorbent assay, and the correlation between these molecules was statistically analyzed.Results: The pediatric adenoids were found to be exposed to bacteria and had a normal flora comprising both gram-negative and -positive bacteria. IL-17RE, an IL-17C specific receptor, was highly expressed in the epithelium of adenoids. IL-17C was expressed in all evaluated adenoid tissue samples, irrespective of the allergic status of the patient. IL-17C secretion was detected in half of the adenoid lavage fluid samples and was associated with Hsp70 level.Conclusion: Our findings indicate the possible role of pediatric adenoids in innate immunity modulation via an innate immunity-associated cytokine.

Co-infection of Mycoplasma gallisepticum and Escherichia coli Triggers Inflammatory Injury Involving the IL-17 Signaling Pathway.

Mycoplasma gallisepticum and Escherichia coli are well known respiratory disease-inducing pathogens. Previous studies have reported that co-infection by MG and E.coli causes significant economic loss in the poultry industry. In order to assess the respiratory toxicity of co-infection in chicken lung, we established a co-infection model to investigate changes in the inflammatory cytokines, lung tissue structure, and transcriptome profiles of chicken lung. The results showed that co-infection caused a wider range of immune damage and more severe tissue lesions than single-pathogen infection. Differentially expressed gene (DEG) analysis indicated that 3,115/1,498/1,075 genes were significantly expressed among the three infection groups, respectively. Gene ontology and KEGG analysis showed genes enriched in response to immune response, cytokine-cytokine receptor interaction, and inflammation-related signaling pathways. Among these pathways, IL-17 signaling was found to be significantly enriched only in co-infection. The expression of IL-17C, CIKS, TRAF6, NFκB, C/EBPβ, and inflammatory chemokines were significantly up-regulated in response to co-infection. Taken together, we concluded that co-infection increased the expression of inflammatory chemokines in lungs through IL-17 signaling, leading to cilia loss and excessive mucus secretion. These results provide new insights into co-infection and reveal target proteins for drug therapy.

Immune modulation, growth performance, and nutrient retention in broiler chickens fed a blend of phytogenic feed additives.

This study aimed to assess the effect of a commercial blend of phytogenic feed additives (PA), comprising 5% carvacrol, 3% cinnamaldehyde, and 2% capsicum oleoresin on the modulation of immune biomarkers of broiler chickens, their growth performance, dietary energy, and nutrient retention. Four-hundred day-old birds were assigned to one of four dietary treatments. Two control diets based on either wheat (WC) or maize (MC) were each given with and without PA at 100g/t. Growth performance variables including feed intake (FI), weight gain (WG), and feed conversion ratio (FCR) were recorded. Dietary N-corrected apparent metabolizable energy (MEn), dry matter (DMR), nitrogen (NR), and fat retention (FR) coefficients were also determined. Gene expression of immune biomarkers (cytokines) were determined in caecal tonsil tissue from 21 d old birds. Expression of IL2, IL18, IL10, and IL17C in the caecal tonsils were upregulated (P < 0.05) in the birds fed MC-based diets compared to the WC fed birds. Feeding PA supplemented diets downregulated the expression of CD40LG (P < 0.001), IFNG, and IL6 (P < 0.05). There was a cereal type × PA interaction (P < 0.05), as expression of IFNB was downregulated in the birds fed PA supplemented MC but not WC. However, expression of IL12B was downregulated in birds fed PA supplemented WC but there was no significant (P > 0.05) change in expression levels in birds fed MC diets. Feeding MC diets gave greater FI (P < 0.001) and ME (P < 0.05), but lower FCR (P < 0.05) compared to birds fed WC diets. The WG and nutrient retention coefficients were not affected (P > 0.05) by cereal type. Supplementary PA improved FI (P < 0.05), WG (P < 0.001), FCR (P < 0.05), MEn (P < 0.05), MEn: GE ratio (P < 0.05), and FR (P < 0.05). In conclusion, dietary inclusion of PA improved overall growth performance variables, energy, and nutrient retention and intestinal cytokine expression.

Transcriptome analysis reveals the role of the PCP pathway in fipronil and endotoxin-induced lung damage

BackgroundPesticide residues in food and environment along with airborne contaminants like endotoxins pose a tangible threat to living beings. Fipronil, a broad-spectrum insecticide at acute doses in combination with endotoxin has been linked to airway inflammation. Wnt/PCP pathway plays important role in the pathogenesis of chronic inflammatory conditions by contributing to the release of downstream cytokines. However, there is no data on the PCP signaling pathway during fipronil-induced lung damage. This study aims to understand the molecular mechanisms underlying the pulmonary toxicity induced by fipronil alone or in combination with endotoxin.MethodsWe used a microarray approach to obtain a global view of the transcriptional responses of the lungs exposed to fipronil and endotoxin in a mice model. Lung tissues were harvested from male Swiss albino mice (n=42) following long term oral exposure to high and low doses of fipronil alone or in combination with endotoxin. The differentially expressed genes were analyzed by Ingenuity pathway analysis software to predict the top canonical pathways. The microarray data for selected genes was validated using quantitative PCR and immunohistochemistry.ResultsBoth BAL fluid and histopathology analysis suggested lung damage and altered transcriptomic profile of lung following exposure to high and low dose of fipronil with or without endotoxin. PCP pathway was among the top upregulated canonical pathways following exposure to both doses of fipronil individually or with LPS. Low dose of fipronil increased the expression of WNT-6, MAPK-8, IL-4 and IL-17C while higher dose decreased the expression of MAPK-8 and IL-17C. The expression data verified by realtime PCR was in concordance with microarray data.ConclusionLong-term exposure to low (4.75 mg kg-1) and high (9.50 mg kg-1) dose of fipronil alone or in combination with endotoxins alters the histoarchitecture and transcriptome profile of lungs with the involvement of the PCP pathway. PCP pathway showed higher enrichment in low dose group of fipronil alone or in combination with LPS. The data from the study provides the insights of the potential damage on lungs caused by fipronil and endotoxin interaction and helps to better understand the mechanism of this complex relation.

IL-17A-mediated expression of epithelial IL-17C promotes inflammation during acute Pseudomonas aeruginosa pneumonia

IL-17A-mediated expression of epithelial IL-17C promotes inflammation during acute Pseudomonas aeruginosa pneumonia

Interleukin-9 and interleukin-17C in chronic rhinosinusitis.

Interleukin (IL)-9 and IL-17C have been known to play a role in allergic inflammation, yet, their roles in chronic rhinosinusitis (CRS) are not well defined. IL-9 induces changes in epithelial cell gene expression leading to goblet cell metaplasia, whereas IL-17C is functionally distinct in that its expression can be induced by bacterial challenge and inflammatory stimuli. This study aimed to compare levels of IL-9 and IL-17C in CRS with nasal polyps (CRSwNP) and without nasal polyps (CRSsNP) as well as atopy. Nasal polyp or sinus mucosal specimens from CRSwNP (n = 36), CRSsNP (n = 9), and control (n = 9) groups were collected and processed. Patient atopy status was determined by history of skin-prick test and pulmonary function test. Immunohistochemistry was carried out using anti-human IL-9 and IL-17C antibodies. Positively-stained cells were enumerated under high-power (×400) magnification in 5 consecutive fields. The level of expression of IL-9 was higher in CRSwNP than CRSsNP and control. Similar findings were demonstrated in IL-17C with higher expression in CRSwNP than CRSsNP and control. Both the averages of positively-stained cells expressing IL-9 and IL-17C were higher in CRS with asthma and allergy compared to control. This suggested that IL-9 and IL-17C were both involved in the pathogenesis of CRS, allergy, and asthma. Inflammatory cell expression of IL-9 and IL-17C were increased in CRS, particularly with allergy and asthma. These interleukins may contribute to the pathogenesis of CRSwNP as well as atopy and may serve as therapeutic targets for disease management.

Interleukin-17C and psoriasis

Interleukin (IL)-17C,a multifunctional cytokine derived from epithelial cells,is different from the other IL-17 family members.There is a preferential and inductive expression of IL-17C in multiple infections and inflammatory reactions.By specifically binding to its high-affinity receptor,IL-17C can act on target cells or interact on other cytokines in an autocrine manner,induce the expressions of antimicrobial peptides,pro-inflammatory cytokines and chemokines.It is involved in the initiation of multiple diseases of epithelial origin (including psoriasis),and may play an important role in their pathogenesis.The authors review the biological function of IL-17C and its relationship with psoriasis. Key words: Psoriasis; Interleukin-17C; Epithelial cells

Vesicular LL-37 contributes to inflammation of the lesional skin of palmoplantar pustulosis.

“Pustulosis palmaris et plantaris”, or palmoplantar pustulosis (PPP), is a chronic pustular dermatitis characterized by intraepidermal palmoplantar pustules. Although early stage vesicles (preceding the pustular phase) formed in the acrosyringium contain the antimicrobial peptides cathelicidin (hCAP-18/LL-37) and dermcidin, the details of hCAP-18/LL-37 expression in such vesicles remain unclear. The principal aim of the present study was to clarify the manner of hCAP-18/LL-37 expression in PPP vesicles and to determine whether this material contributed to subsequent inflammation of lesional skin. PPP vesicle fluid (PPP-VF) induced the expression of mRNAs encoding IL-17C, IL-8, IL-1α, and IL-1β in living skin equivalents, but the level of only IL-8 mRNA decreased significantly upon stimulation of PPP vesicle with depletion of endogenous hCAP-18/LL-37 by affinity chromatography (dep-PPP-VF). Semi-quantitative dot-blot analysis revealed higher concentrations of hCAP-18/LL-37 in PPP-VF compared to healthy sweat (2.87±0.93 µM vs. 0.09±0.09 µM). This concentration of hCAP-18/LL-37 in PPP-VF could upregulate expression of IL-17C, IL-8, IL-1α, and IL-1β at both the mRNA and protein levels. Recombinant hCAP-18 was incubated with dep-PPP-VF. Proteinase 3, which converts hCAP-18 to the active form (LL-37), was present in PPP-VF. Histopathological and immunohistochemical examination revealed that early stage vesicles contained many mononuclear cells but no polymorphonuclear cells, and the mononuclear cells were CD68-positive. The epidermis surrounding the vesicle expresses monocyte chemotactic chemokine, CCL2. In conclusion, PPP-VF contains the proteinase required for LL-37 processing and also may directly upregulate IL-8 in lesional keratinocytes, in turn contributing to the subsequent inflammation of PPP lesional skin.

High IL-17E and low IL-17C dermal expression identifies a fibrosis-specific motif common to morphea and systemic sclerosis.

BackgroundHigh interleukin (IL)-17A levels are characteristically found in the skin of systemic sclerosis (SSc) individuals. Our aim was to investigate whether the dermal expression of IL-17A and related IL-17 family members (i.e. IL-17C, IL-17E and IL-17F) could distinguish fibrotic from healthy skin and could show similarities in SSc and morphea, two disorders with presumed distinct pathogenesis, but characterized by skin fibrosis.MethodsBiopsies were obtained from the involved skin of 14 SSc, 5 morphea and 8 healthy donors (HD) undergoing plastic surgery. Immunohistochemistry/immunofluorescence techniques were coupled to a semi-automated imaging quantification approach to determine the presence of the IL-17 family members in the skin. The in vitro effects induced by the IL-17 family members on fibroblasts from normal and SSc individuals were assessed by ELISA and RIA.ResultsPositive cells for each of the IL-17 isoforms investigated were present in the dermis of all the individuals tested, though with variable frequencies. SSc individuals had increased frequency of IL-17A+ (p = 0.0237) and decreased frequency of IL-17F+ (p = 0.0127) and IL-17C+ cells (p = 0.0008) when compared to HD. Similarly, morphea individuals had less frequent IL-17C+ cells (p = 0.0186) in their skin but showed similar number of IL-17A+ and IL-17F+ cells when compared to HD. Finally, IL-17E+ cells were more numerous in morphea (p = 0.0109) and tended to be more frequent in SSc than in HD. Fibroblast production of IL-6, MMP-1 and MCP-1 was enhanced in a dose-dependent manner in the presence of IL-17E and IL-17F, but not in the presence of IL-17C. None of the cytokine tested had significant effect on type I collagen production. Of interest, in SSc the frequency of both IL-17A and IL-17F positive cells increased with disease duration.ConclusionsThe frequency of IL-17A and IL-17F distinguish SSc to morphea individuals while dermal expression of IL-17C (low) and IL-17E (high) identifies a fibrosis-specific motif. The specific IL-17C/IL-17E cytokine combination may thus play a role in the development of fibrosis.

Polarized secreted IL-17C is a mediator of respiratory epithelial innate immune response

The IL-17 family of cytokines consists of at least six members (IL-17A to -F). IL-17 directly activates epithelial cells leading to the expression of inflammatory mediators and antimicrobial factors. In this study, our aim was to examine the expression and function of IL-17C in respiratory epithelial cells during bacterial infection. In vitro studies showed that common bacterial pathogens, such as Pseudomonas aeruginosa and Haemophilus influenzae, and ligands of Toll-like receptors 3 and 5 (flagellin, polyI:C) induced the expression and release of IL-17C in cultured human bronchial epithelial cells. Differentiated bronchial epithelial cells secreted IL-17C into the basolateral compartment and the secretion of IL-17C was increased in response to basolateral stimulation as compared to apical stimulation with bacterial stimuli. Pharmacological inhibition of intracellular calcium release and calcium chelators inhibited the secretion of IL-17C whereas the release of the inflammatory mediator IL-6 was not affected. IL-17C enhanced inflammatory responses of respiratory epithelial cells infected with P. aeruginosa. These data show that calcium-dependent signaling cascades mediate the polarized secretion of IL-17C and that IL-17C mediates innate immune responses of respiratory epithelial cells.