IL-17 Isoforms Research Articles

Bimekizumab-bkzx for the Treatment of Plaque Psoriasis: A Drug Review.

Bimekizumab is a biologic targeting interleukin (IL)-17A/17F, approved by the Food and Drug Administration (FDA) for moderate-to-severe plaque psoriasis in 2023. A PubMed search was performed using the keywords "bimekizumab," "plaque psoriasis," and "bimekizumab clinical trials," from origin to August 1, 2024. We included phase I to III trials of bimekizumab for plaque psoriasis, studies published post-FDA approval, and information from the package insert. We summarized 1 phase I, 4 phase II, and 4 phase III trials, and 3 real-world studies published post-FDA approval. Bimekizumab was effective; >85% and 70% of patients achieved PASI90 and PASI100, respectively, in phase III trials. Head-to-head, 85% of bimekizumab patients achieved PASI90 versus 50% of ustekinumab patients. The most frequent adverse event was oral candidiasis (4%-10%); serious adverse events were rare (<1%). Long-term studies confirmed sustained efficacy and consistent safety profile. Bimekizumab was more efficacious than other IL-17 inhibitors, ustekinumab, and adalimumab. Real-world data corroborate bimekizumab's efficacy. Bimekizumab had a safety profile like other IL-17 inhibitors, with higher rates of mucocutaneous candidiasis. Many patients who failed other IL-17 inhibitors and switched to bimekizumab experienced clearance. The efficacy of bimekizumab in patients who failed other IL-17 blockers may be attributable to bimekizumab's ability to block multiple IL-17 isoforms. Bimekizumab also outperformed tumor necrosis factor (TNF)-alpha inhibitors. There may be patients who fail previously available drugs, for reasons including nonadherence, antidrug antibodies, or adverse effects; bimekizumab, which targets additional cytokines, may bridge that gap.

Preliminary Investigation and Therapeutic Efficacy Determination of a Novel Anti-IL-17A Antibody, Indikizumab.

The study aimed to develop and characterize Indikizumab, a novel humanized anti-IL-17A monoclonal antibody (mAb), for potential therapeutic use in inflammatory indications such as psoriasis, psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis. The research involved the purification of IL-17 isoforms, epitope mapping, affinity ranking, and comparative binding assessment of anti-IL-17 antibodies. The study also included cell-based neutralization assays and in vivo studies using mouse models to evaluate the efficacy of Indikizumab. Indikizumab demonstrated a high binding affinity (KD=27.2 pM) and specificity for IL-17A, with comparable potency to Secukinumab. In cell-based neutralization assays, Indikizumab effectively neutralized the effects of IL-17A and demonstrated a statistically significant reduction in plasma KC (Keratinocyte) levels in a mouse model. In imiquimod-induced psoriasis mouse model, Indikizumab showed potential in reducing the psoriasis index. Indikizumab represents a promising therapeutic option for inflammatory indications with its high binding affinity, specificity for IL-17A, and effectiveness in neutralizing IL-17A effects in vivo.

038 Single-cell sequencing of freshly isolated cells from lesional and peri-lesional skin to explore cellular origins of IL-17 isoforms in psoriasis

Psoriasis is the most common chronic inflammatory skin disease in adults, characterized by immune cell infiltration, expansion of disease-associated lymphocytes, and epidermal hyperplasia. Increasing evidence highlights the central role of interleukin (IL)-17A and IL-17F in its pathobiology. IL-17A and IL-17F, known to be produced by activated T helper 17 cells, can form homodimers or heterodimers to drive aberrant keratinocyte biology. We applied single-cell RNA sequencing to characterize the immune infiltrate of psoriatic skin and further understand cellular sources of IL-17A and IL-17F.

IL-17A, IL-17E and IL-17F as Potential Biomarkers for the Intensity of Low-Grade Inflammation and the Risk of Cardiovascular Diseases in Obese People.

Low-grade inflammation is a factor that predisposes to many obesity-related comorbidities. The immune mechanisms controlling the inflammatory response related to the secretory activity of adipocytes and its consequences for the organism are still under investigation. Methods: 84 obese adult volunteers (BMI ≥ 30 kg/m2) were tested by BIA. Serum samples were collected to analyze the concentrations of interleukins IL-17A, IL-17E and IL-17F. The subjects completed the original questionnaire, the FFQ-6 food consumption frequency questionnaire and the food diary. Results: The level of IL-17E and IL-17F was positively correlated with the BMI value and the level of IL-17E increased with the content of subcutaneous fat. Its increased blood concentration was also observed in individuals who declared that they were diagnosed with atherosclerosis and/or were taking beta-blockers. Products that were related with a low level of the above-mentioned interleukins were vegetables, groats, eggs, red meat, fast-food and alcohol. The level of these interleukins was positively correlated with the frequent consumption of confectionery and breakfast cereals. Nutrients that decreased the concentrations of IL-17 isoforms were potassium, iron, vitamins B6 and C, and folic acid. Conclusions: Both IL-17E and IL-17F may be closely related to the intensity of low-grade inflammation and be biomarkers of cardiovascular disease risk. Food products or the nutrients they contain may affect the levels of the above-mentioned interleukins as well as IL-17A.

From Messengers to Receptors in Psoriasis: The Role of IL-17RA in Disease and Treatment.

The paradigm of psoriasis as a Th17-driven disease has evolved in the last years towards a much deeper knowledge of the complex pathways, mechanisms, cells, and messengers involved, highlighting the crucial role played by the IL-17 family of cytokines. All IL-17 isoforms signal through IL-17R. Five subunits of IL-17R have been described to date, which couple to form a homo- or hetero-receptor complex. Characteristically, IL-17RA is a common subunit in all hetero-receptors. IL-17RA has unique structural—containing a SEFIR/TILL domain—and functional—requiring ACT-1 for signaling—properties, enabling Th17 cells to act as a bridge between innate and adaptive immune cells. In psoriasis, IL-17RA plays a key role in pathogenesis based on: (a) IL-17A, IL-17F, and other IL-17 isoforms are involved in disease development; and (b) IL-17RA is essential for signaling of all IL-17 cytokines but IL-17D, whose receptor has not been identified to date. This article reviews current evidence on the biology and role of the IL-17 family of cytokines and receptors, with focus on IL-17RA, in psoriasis and some related comorbidities, and puts them in context with current and upcoming treatments.

Interleukin (IL)-12 and IL-18 Synergize to Promote MAIT Cell IL-17A and IL-17F Production Independently of IL-23 Signaling.

IL-23 is considered a critical regulator of IL-17 in Th17 cells; however, its requirement for inducing IL-17 production in other human immune subsets remains incompletely understood. Mucosal associated invariant T (MAIT) cells uniformly express retinoic acid receptor-related orphan receptor gamma t (RORγt) but only a minor population have been shown to produce IL-17A. Here we show that IL-17F is the dominant IL-17 isoform produced by MAIT cells, not IL-17A. For optimal MAIT cell derived IL-17A and IL-17F production, T cell receptor (TCR) triggering, IL-18 and monocyte derived IL-12 signaling is required. Unlike Th17 cells, this process is independent of IL-23 signaling. Using an in vitro skin cell activation assay, we demonstrate that dual neutralization of both IL-17A and IL-17F resulted in greater suppression of inflammatory proteins than inhibition of IL-17A alone. Finally, we extend our findings by showing that other innate-like lymphocytes such as group 3 innate lymphoid cells (ILC3) and gamma delta (γδ) T cells are also capable of IL-23 independent IL-17A and IL-17F production. These data indicate both IL-17F and IL-17A production from MAIT cells may contribute to tissue inflammation independently of IL-23, in part explaining the therapeutic disconnect between targeting IL-17 or IL-23 in certain inflammatory diseases.

Characteristic Pattern of IL-17RA, IL-17RB, and IL-17RC in Monocytes/Macrophages and Mast Cells From Patients With Bullous Pemphigoid.

Inflammation is largely implicated in bullous pemphigoid (BP), the most frequent skin auto-immune blistering disease. IL-17, essentially IL-17A/F, has been involved in blister formation through regulation of protease production, and its specific serum profile within BP was related to disease outcome. However, relationships between IL-17 family ligands and receptors are quite complex with six different IL-17 isoforms, and five different receptors. We here aimed at clarifying the contribution of the IL-17 axis in BP by characterizing not only the expression of IL-17 receptor (IL-17R) members within immune cells isolated from BP patients (PMNs, n = 9; T-lymphocytes, n = 10; and monocytes, n = 10) but also the expression of IL-17 isoforms in sera (n = 83), and blister fluid (n = 31) of BP patients. We showed that at diagnosis, IL-17RA and IL-17RC expression were significantly increased in monocytes isolated from BP patients as compared to those from control subjects (p = 0.006 and p = 0.016, respectively). Notably, both IL-17RA and IL-17RC mRNA expression remained elevated in BP monocytes at time of relapse. We further demonstrated a significant increase of all IL-17 isoforms tested in BP blister fluid compared with BP serum (IL-17A, p < 0.0001; IL-17A/F, p < 0.0001; IL-17B, p = 0.0023; IL-17C, p = 0.0022; IL-17E, p < 0.0001). Among all, IL-17B was the only cytokine for which a significant decreased concentration within blister fluid was observed in BP patients with severe disease compared to patients with moderate disease (p = 0.012). We further evidenced a significant negative correlation between IL-17B levels and blister/erosion BPDAI subscore (r = −0.52, p = 0.003). We finally identified mast cells as a potential target of IL-17B in lesional skin of BP patients. In conclusion, we showed here that IL-17RA and IL-17RC expression in monocyte was associated with disease activity and evidenced in situ a negative correlation between BP disease activity and IL-17B, whose effects could be mediated by IL-17RB expressed by mast cell in BP lesional skin.

207 IL-17E (IL-25) alters epidermal homeostasis in a matter distinct from IL-17A

Our group has recently shown that keratinocyte-derived IL-17E (IL-25), one of six IL-17 isoforms, is overexpressed in lesional psoriatic skin. The presence of a complete receptor for IL-17E at the keratinocyte surface indicates the potential autocrine mode of action of the cytokine. We therefore aimed at addressing the influence of IL-17E on the functions of human primary keratinocytes. First, IL-17E, but not IL-17A, promoted the proliferation of keratinocytes as assessed by WST-1 proliferation assay and crystal violet staining. Surprisingly, IL-17E addition to cultured keratinocytes resulted in the concomitant up-regulation of differentiation-associated gene transcripts (i.e. keratin 10, loricrin and filaggrin), while their expression was either inhibited or not changed by IL-17A. Immunohistochemical analysis of in vitro reconstituted 3D epidermal equivalents confirmed these results. IL-17E, contrary to IL-17A, was instead not involved in the induction of an antimicrobial response. Moreover, time-lapse analysis of cell movement showed that IL-17E particularly influences cell motility increasing both cell speed and displacement. This was associated with specific changes in actin cytoskeleton organization and regulation of proteins involved in the focal contacts assembly such as vinculin. Altogether, our data point towards an important role for IL-17E in the epidermal phenotype of psoriasis; this role is clearly distinct from the role of IL-17A. Our results also reveal a possible effect of IL-17E beyond psoriasis, in disorders characterized by epidermal alterations as well as in the wound healing process.

Measurement of level of vitamin D and Antioxidants in Discoid Lupus Erythematosus patients

DISCOID Lupus Erythematosus (DLE) is a chronic dermatological disease that can lead to scarring, hair loss, and hyperpigmentation changes in skin if it is not treated early and promptly. Diagnosis of discoid lupus is generally made based on clinical features. Sometimes, tests are required, including blood and urine samples. Similar to other many autoimmune conditions, DLE is generally a lifelong condition. However, there are treatments available that are usually effective and can help keep symptoms under control. IL-17 isoforms (IL-17A and IL-17F) are implicated in DLE.Active Vitamin D3 (1, 25(OH) 2D3) is a fat-soluble vitamin that its principle action is to increase the absorption of calcium and phosphate ions from the intestine and directly affect the calcification process. Beside its crucial role in calcium metabolism and bone remodeling, active vitamin D3 is considered an immunomodulator. Increased reactive oxygen species (ROS), lipid peroxides, and low antioxidant status occur in autoimmune disorder.This study aims to assess the level of vitamin D3 [25(OH) D3] in Discoid Lupus Erythematosus (DLE) patients compared to normal controls, its correlation with disease activity parameters, laboratory parameters and antioxidants levels.Twenty patients with (DLE) and 20 healthy controls matched for age and gender were included into this prospective study. Serum vitamin D3 [25(OH) D3] is measured as it is the precursor of active vitaminD3 [1, 25(OH) 2D3] which has a very short half-life. Oxidative stress was assessed by measuring serum malondialdehyde (MDA) and enzymatic antioxidant status by estimating superoxide dismutase (SOD) and glutathione peroxidase (GPX).The results of the present work are highly suggestive of the importance of vitamin D3 supplementation in (DLE) and the importance of topical antioxidants to control flare in DLE patients.The serum levels of vitamin D3, SOD, and GPX were significantly lower in DLE patients when compared to their levels in the control group (p< 0.000) .On the other hand, MDA was significantly higher in the DLE patients than that in the healthy control subjects (p<0.001). A highly statistical negative correlation between vitamin D3 with MDA level (P <0.004and r = -0.615) was observed. On the other hand, SOD and GPX positively correlated with vitamin D3 level (P < 0.001 and P<0.000 respectively and r = 0.680 and 0.734 respectively).It could be suggested that low vitamin D3 and disturbed antioxidant levels are prevalent in the Egyptian DLE patients. There is a clear association between vitamin D3 and antioxidants with different signs of disease activity. A routine vitamin D3 and antioxidant supplementations are recommended to DLE patients for better prognosis.

Interleukin-17A is involved in mechanical hyperalgesia but not in the severity of murine antigen-induced arthritis

Interleukin-17A (IL-17A) is considered an important pro-inflammatory cytokine but its importance in joint diseases such as rheumatoid arthritis (RA) is unclear. It has also been reported that IL-17A may induce pain but it is unclear whether pro-inflammatory and pro-nociceptive effects are linked. Here we studied in wild type (WT) and IL-17A knockout (IL-17AKO) mice inflammation and hyperalgesia in antigen-induced arthritis (AIA). We found that the severity and time course of AIA were indistinguishable in WT and IL-17AKO mice. Furthermore, the reduction of inflammation by sympathectomy, usually observed in WT mice, was preserved in IL-17AKO mice. Both findings suggest that IL-17A is redundant in AIA pathology. However, in the course of AIA IL-17AKO mice showed less mechanical hyperalgesia than WT mice indicating that IL-17A contributes to pain even if it is not crucial for arthritis pathology. In support for a role of IL-17A and other members of the IL-17 family in the generation of pain we found that sensory neurones in the dorsal root ganglia (DRG) express all IL-17 receptor subtypes. Furthermore, in isolated DRG neurones most IL-17 isoforms increased tetrodotoxin- (TTX-) resistant sodium currents which indicate a role of IL-17 members in inflammation-evoked sensitization of sensory nociceptive neurones.

Unmet Needs in the Field of Psoriasis: Pathogenesis and Treatment.

In times of targeted therapies, innovative therapeutics become tools to further unravel the pathogenesis of the treated disease, thus influencing current pathogenetic concepts. Based on such paradigm shifts, the next generation of novel therapeutic targets might be identified. Psoriasis is a good example for the resulting most fruitful dialog between clinical and fundamental research. As a result of this, the key role of Th17 lymphocytes, some of their effector molecules, as well as mediators contributing to their maturation have been identified, many of these being targeted by some of the most effective drugs currently available to treat psoriasis. During this process, it became obvious that major parts of the puzzle remain yet to be uncovered or understood in much more detail. This review will therefore address the search for additional important effector cells other than Th17 lymphocytes, such as neutrophils, monocytes, and mast cells, mediators other than IL-17A, including some other IL-17 isoforms, and trigger factors such as potential autoantigens. This will lead to discussing the next generation of targeted therapies for psoriasis as well as treatment goals. These goals need to comprise both psoriasis as well as its comorbidities, as a comprehensive approach to manage the whole patient with all his health issues is urgently needed. Finally, given the substantial differences in resources available in different parts of the world, the global burden of psoriasis and options on how to care for patients outside developed countries will be assessed.

Brodalumab: The first anti-IL-17 receptor agent for psoriasis

Psoriasis is a chronic immune-mediated inflammatory skin disease in which the alteration of the interleukin-23 (IL-23)/IL-17 cytokine axis appears to be crucial from a pathogenetic perspective. This has been confirmed by the efficacy of monoclonal antibodies blocking IL-17A, such as secukinumab and ixekizumab. Brodalumab is a human anti-IL-17 receptor A (IL-17RA) monoclonal antibody that inhibits the biological activity of IL-17A, IL-17F and other IL-17 isoforms, and has been approved (210 mg s.c. at weeks 0, 1, 2 and every 2 weeks thereafter) for the treatment of psoriasis vulgaris, psoriatic arthritis, pustular psoriasis and psoriatic erythroderma in Japan (Lumicef). The U.S. Food and Drug Administration has also recently approved brodalumab (Siliq) for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy and have failed to respond or have lost response to other systemic therapies. Regulatory applications are under review in the E.U. and Canada. The phase III clinical trials in moderate to severe plaque psoriasis met their primary endpoints after 12 weeks' treatment, with PASI 75 (75% improvement in the Psoriasis Area and Severity Index) response rates ranging between 83% and 86% (210 mg) and PASI 100 response rates ranging between 37% and 44%, significantly higher than those achieved with ustekinumab in the head-to-head trials AMAGINE-1 and AMAGINE-2. The most frequently reported adverse events in brodalumab clinical trials consisted of nasopharyngitis, headache, upper respiratory tract infection and arthralgia. In the head-to-head trials, rates of neutropenia were higher with both active drugs than with placebo, and mild or moderate Candida infections were more frequent with brodalumab than with ustekinumab or placebo. Clinical development was terminated by Amgen after adverse events of suicidal ideation and behavior were observed ls involving several indications, but data are inconclusive regarding potential drug causality, and brodalumab has recently been approved in the U.S. with a black box warning and a risk-management program regarding suicidal issues. Blocking IL-17RA provides a highly efficacious therapeutic alternative for moderate to severe psoriasis with a satisfactory safety profile.

Role of IL-17A in murine models of COPD airway disease.

Small airway fibrosis is a major pathological feature of chronic obstructive pulmonary disease (COPD) and is refractory to current treatments. Chronic inflammatory cells accumulate around small airways in COPD and are thought to play a major role in small airway fibrosis. Mice deficient in α/β T cells have recently been shown to be protected from both experimental airway inflammation and fibrosis. In these models, CD4+Th17 cells and secretion of IL-17A are increased. However, a pathogenic role for IL-17 in specifically mediating fibrosis around airways has not been demonstrated. Here a role for IL-17A in airway fibrosis was demonstrated using mice deficient in the IL-17 receptor A (il17ra) Il17ra-deficient mice were protected from both airway inflammation and fibrosis in two different models of airway fibrosis that employ COPD-relevant stimuli. In these models, CD4+ Th17 are a major source of IL-17A with other expressing cell types including γδ T cells, type 3 innate lymphoid cells, polymorphonuclear cells, and CD8+ T cells. Antibody neutralization of IL-17RA or IL-17A confirmed that IL-17A was the relevant pathogenic IL-17 isoform and IL-17RA was the relevant receptor in airway inflammation and fibrosis. These results demonstrate that the IL-17A/IL-17 RA axis is crucial to murine airway fibrosis. These findings suggest that IL-17 might be targeted to prevent the progression of airway fibrosis in COPD.

IL-17 A AND F ISOFORMS AND THEIR RECEPTORS IN EXPERIMENTAL CHOLESTASIS AND THE IL17A/F HETERODIMER INDUCES A PROFIBROGENIC PROFILE IN HEPATIC STELLATE CELLS IN VITRO

Event Abstract Back to Event IL-17 A AND F ISOFORMS AND THEIR RECEPTORS IN EXPERIMENTAL CHOLESTASIS AND THE IL17A/F HETERODIMER INDUCES A PROFIBROGENIC PROFILE IN HEPATIC STELLATE CELLS IN VITRO Miriam R. Bueno-Topete1*, Sara M. Zepeda-Morales1, Susana Del Toro-Arreola1, Leonel Garcia2, Alejandra N. Vega-Magaña1, Blanca E. Bastidas-Ramírez1 and Mary Fafutis-Morris3 1 Universidad de Guadalajara, Biología Molecular y Genómica, Mexico 2 Universidad de Guadalajara, Fisiología, Mexico 3 Universidad de Guadalajara, Fisiología, Mexico Background. IL-17 plays a central role in the pathogenesis of fibrosis associated with various etiologies. Significant decrease in liver fibrosis in IL-17RA knockout mice has been demonstrated. However, the expression of IL-17 isoforms and their receptors in cholestatic liver fibrosis has not been explored yet. Aditionally, there is not enough information about IL-17A/F heterodimer in vitro signaling on hepatic stellate cells (HSC). Objetives. To analyze the expression of IL-17A, IL-17F and their receptors IL-17RA and IL-17RC in the liver of rats with cholestasis; aditionally we investigated the participation of IL-17A/F on HSC signaling. Methods. Male Wistar rats were sacrificed at 8 and 30d after bile duct ligation (BDL). Hepatic IL-17A, IL17-F, IL-17RA and IL-17RC expression was determined by qRT-PCR. Protein levels of IL-17 and RORgammaT were analyzed by Western Blot. Activated HSC were stimulated with IL-17A/F, then the transcriptional factors Stat-3p, NF-κB and Smad-2p and profibrogenic genes collagen I, III and TGF-beta were evaluated by qRT-PCR. Results. Hepatic gene expression of IL-17A, IL-17-F and IL-17RC dramatically increased at 8 and 30d post BDL. IL- 17RA significantly increased at 30d post BDL. The overall IL-17RC level was positively correlated with both IL-17A and IL-17F. At the protein level, IL-17 and RORgammaT significantly increased 8 and 30d post BDL. In vitro, Stat-3p, NF-kB, Smad-2p and collagen I, III and TGF-beta significantly increased in HSC stimulated with IL-17A/F. Conclusions. IL-17 (A and F) isoforms and their receptors are critical mediators of liver damage in experimental cholestatic fibrosis. Th17 cells might represent an important source of IL-17. Heterodimeric IL-17A/F potentially induces profibrogenic genes in HSC cultures. References Meng F, Wang K, Aoyama T, Grivennikov SI, Paik Y, Scholten D, Cong M, et al. Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology. 2012; 143:765–76. Harada K, Shimoda S, Sato Y, Isse K, Ikeda H, Nakanuma Y. Periductal interleukin-17 production in association with biliary innate immunity contributes to the pathogenesis of cholangiopathy in primary biliary cirrhosis. Clin Exp Immunol. 2009; 157:261–70. Keywords: IL-17 isoforms, liver fibrosis, RORγt, IL-17 RECEPTORS, Hepatic Stellate Cells Conference: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología, Medellin, Colombia, 13 Oct - 16 Oct, 2015. Presentation Type: Poster Presentation Topic: Adaptive Immunity Citation: Bueno-Topete MR, Zepeda-Morales SM, Del Toro-Arreola S, Garcia L, Vega-Magaña AN, Bastidas-Ramírez BE and Fafutis-Morris M (2015). IL-17 A AND F ISOFORMS AND THEIR RECEPTORS IN EXPERIMENTAL CHOLESTASIS AND THE IL17A/F HETERODIMER INDUCES A PROFIBROGENIC PROFILE IN HEPATIC STELLATE CELLS IN VITRO. Front. Immunol. Conference Abstract: IMMUNOCOLOMBIA2015 - 11th Congress of the Latin American Association of Immunology - 10o. Congreso de la Asociación Colombiana de Alergia, Asma e Inmunología. doi: 10.3389/conf.fimmu.2015.05.00049 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 15 Apr 2015; Published Online: 14 Sep 2015. * Correspondence: Prof. Miriam R Bueno-Topete, Universidad de Guadalajara, Biología Molecular y Genómica, Guadalajara, Jalisco, Mexico, ruthmyriamtop@hotmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Miriam R Bueno-Topete Sara M Zepeda-Morales Susana Del Toro-Arreola Leonel Garcia Alejandra N Vega-Magaña Blanca E Bastidas-Ramírez Mary Fafutis-Morris Google Miriam R Bueno-Topete Sara M Zepeda-Morales Susana Del Toro-Arreola Leonel Garcia Alejandra N Vega-Magaña Blanca E Bastidas-Ramírez Mary Fafutis-Morris Google Scholar Miriam R Bueno-Topete Sara M Zepeda-Morales Susana Del Toro-Arreola Leonel Garcia Alejandra N Vega-Magaña Blanca E Bastidas-Ramírez Mary Fafutis-Morris PubMed Miriam R Bueno-Topete Sara M Zepeda-Morales Susana Del Toro-Arreola Leonel Garcia Alejandra N Vega-Magaña Blanca E Bastidas-Ramírez Mary Fafutis-Morris Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

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.

CD4+ Th17 cells discriminate clinical types and constitute a third subset of non Th1, Non Th2 T cells in human leprosy.

BackgroundPatients with localized tuberculoid and generalized lepromatous leprosy show respectively Th1 and Th2 cytokine profile. Additionally, other patients in both types of leprosy also show a non discriminating Th0 cytokine profile with both interferon-γ and IL-4. The present study investigated the role of Th17 cells which appear to be a distinct subtype of Th subtypes in 19 tuberculoid and 18 lepromatous leprosy patients. Five healthy subjects with long term exposure to infection and 4 skin biopsies from healthy subjects undergoing cosmetic surgery were used as controls.Methodology/Principle FindingsAn array of Th17 related primers for cytokines, chemokines and transcription factors was used in real time reverse transcribed PCR to evaluate gene expression, ELISA for cytokine secretion in the supernatants of antigen stimulated PBMC cultures and flow cytometry for establishing the phenotype of the IL-17, IL-21 producing cells.Conclusions/SignificanceIL-17 isoforms showed significantly higher expression and release in supernatants of antigen stimulated PBMC cultures and dermal lesions of healthy contacts and tuberculoid leprosy as compared to lepromatous leprosy (p<0.003). This was further confirmed by Th17 associated transcription factor RORC, cytokines IL-21, IL-22, and IL-23, chemokines MMP13, CCL20, CCL22. Of interest was the association of IL-23R and not IL-6R with IL-17+ cells. The Th17 cells were CD4+ CCR6+ confirming their effector cell lineage. Polarized Th1 cytokines were seen in 3/7 tuberculoid and Th2 cytokines in 5/10 lepromatous leprosy patients. Of importance was the higher association of Th17 pathway factors with the non-polarized Th0 types as compared to the polarized Th1 and Th2 (p<0.01). Our study draws attention to a third type of effector Th cell that may play a role in leprosy.

AB0687 Th-17 cytokine profile in children with juvenile idiopathic arthritis.

BackgroundTh17 cells have recently been identified as important in pathogenesis of chronic arthritis including juvenile idiopathic arthritis (JIA). Th17 are highly proinflammatory subset of T cells, characterised by production of...

Tu1616 Rpc1063 Is a Potent S1p1r Agonist With Efficacy in the Samp1yitfc Ileitis Model: New Evidence for Dysregulation of S1p Metabolism in Preclinical Models and Patients With Inflammatory Bowel Disease

Body: Synthetic triterpenoids are effective anti-cancer agents. They also inhibit IL17 and improve autoimmune disease in mice, but have not been tested in murine IBD models. One prototype triterpenoid, CDDO-Im, inhibits STAT3 pathway activation. This transcription factor plays a role in the pathogenesis of IBD. Aims: The goals of the study were two-fold: To determine if ex vivo treatment with CDDO-Im would be effective for attenuating colonic IL-17 isoform secretion; and to determine if oral treatment with CDDOIm would modulate colonic IL-17 and improve DSS-induced colitis in mice. Methods: Study 1: Colitis was induced in male C57BL/6 mice (n = 9) by adding DSS 2% to the drinking water for 6 days. A control group of mice (n = 4) received filtered water. On day 6, colons were collected and organ culture was performed. Colonic strips (3 mm) were exposed to CDDO-Im at 0.5, 1, and 2 μM concentrations in the presence of IL-23 + IL-1 β (10 ng/ml of each). After 24 hours, supernatant was collected. IL-17 andIL-17F were measured by ELISA. Study 2: Using the same colitis paradigm described above, 20 mice were randomized into 3 groups (table 1). Mice were dosed by orogastric gavage with vehicle (10% Cremophor, 10% DMSO, 80% PBS) or CDDO-Im (20mg/kg) on study days 0, 1, 3 and 5. Body weights, water consumption and disease activity index (DAI) scores (0-12 scale) were recorded daily. Colons were collected on day 6. Distal colon was retained for colonic histology. Using coded slides, histology scores were determined with a 40-point severity scale. The proximal colon samples were analyzed for IL-17, IL-17F, IL-6 (by ELISA), and colonic MPO. Colonic nuclear protein extracts were used to measure the binding of STAT3 to a consensus site (specific Trans-Am® kit). Results: In colonic strips from DSS-treated mice, ex vivo treatment with CDDO-Im dose-dependently decreased both IL-17 and IL-17F secretion. The calculated IC50 values were 0.51 μM and 0.62 μM respectively. A similar inhibitory profile was found for CDDO-Im when using colonic strips from non-DSS-treated mice. In vivo, vehicle-treated mice lost weight between study days 2 and 6, while CDDO-treated animals gained weight (table 1). On study day 6, mean DAI, MPO, histology score, IL-17 and IL-6 values were all lower in the CDDO-Im group. These results are consistent with decreased colonic inflammation, compared to Vehicle/DSS treatment. Nuclear binding of STAT3 was also significantly attenuated (p , 0.05) in the CDDO-Im group of mice, compared to the corresponding vehicle cohort of animals. Summary: CDDO-Im attenuated IL-17 isoform secretion in an ex vivo model of colonic inflammation. In vivo, CDDO-Im improved multiple parameters of murine DSS-induced colitis, including STAT3 and IL-17. Conclusion: CDDO-Im has a unique pharmacological profile, which supports further testing in animal models of IBD. Table 1. Treatment Groups S-807 AGA Abstracts Values are Mean ± SEM. + p , 0.05 vs. Vehicle/Water or * p , 0.05 vs. Vehicle/DSS

Keratinocyte Overexpression of IL-17C Promotes Psoriasiform Skin Inflammation

IL-17C is a functionally distinct member of the IL-17 family that binds IL-17 receptor E/A to promote innate defense in epithelial cells and regulate Th17 cell differentiation. We demonstrate that IL-17C (not IL-17A) is the most abundant IL-17 isoform in lesional psoriasis skin (1058 versus 8 pg/ml; p < 0.006) and localizes to keratinocytes (KCs), endothelial cells (ECs), and leukocytes. ECs stimulated with IL-17C produce increased TNF-α and KCs stimulated with IL-17C/TNF-α produce similar inflammatory gene response patterns as those elicited by IL-17A/TNF-α, including increases in IL-17C, TNF-α, IL-8, IL-1α/β, IL-1F5, IL-1F9, IL-6, IL-19, CCL20, S100A7/A8/A9, DEFB4, lipocalin 2, and peptidase inhibitor 3 (p < 0.05), indicating a positive proinflammatory feedback loop between the epidermis and ECs. Psoriasis patients treated with etanercept rapidly decrease cutaneous IL-17C levels, suggesting IL-17C/TNF-α-mediated inflammatory signaling is critical for psoriasis pathogenesis. Mice genetically engineered to overexpress IL-17C in KCs develop well-demarcated areas of erythematous, flakey involved skin adjacent to areas of normal-appearing uninvolved skin despite increased IL-17C expression in both areas (p < 0.05). Uninvolved skin displays increased angiogenesis and elevated S100A8/A9 expression (p < 0.05) but no epidermal hyperplasia, whereas involved skin exhibits robust epidermal hyperplasia, increased angiogenesis and leukocyte infiltration, and upregulated TNF-α, IL-1α/β, IL-17A/F, IL-23p19, vascular endothelial growth factor, IL-6, and CCL20 (p < 0.05), suggesting that IL-17C, when coupled with other proinflammatory signals, initiates the development of psoriasiform dermatitis. This skin phenotype was significantly improved following 8 wk of TNF-α inhibition. These findings identify a role for IL-17C in skin inflammation and suggest a pathogenic function for the elevated IL-17C observed in lesional psoriasis skin.

Therapeutic potential of targeting IL‐17 and IL‐23 in sepsis

Severe sepsis is a major concern of public health in industrialized countries. It is estimated that in the United States 200,000-400,000 cases occur annually and resulting in an extensive burden for the health care systems. To date, no FDA-approved pharmacologic agents for the treatment or prevention of human sepsis are available. The current modalities of therapy in sepsis include the standard arsenal of supportive interventions in critical care medicine and pharmacotherapy, with use of antibiotics and catecholamines. Despite such efforts, the mortality rates of sepsis have remained around 30-50 %. Extensive scientific studies have utilized animal models of disease and aimed for a better understanding of the pathophysiologic mechanisms during sepsis. Members of the IL-17 family of cytokines, as well as the functionally related IL-23, have been identified as new players in the molecular events during sepsis. Strategies for targeting these mediators with neutralizing antibodies during experimental sepsis in rodents have demonstrated efficacy, resulting in improved survival outcomes. Currently, it is not clear whether such findings can be translated to human sepsis. This review highlights the current knowledge on the biology of IL-17 isoforms and IL-23 as well as potential applications to clinical medicine.