Role Of IL-17 In Pathogenesis Research Articles

Elevated levels of IL-6 in IgA nephropathy patients are induced by an epigenetically driven mechanism modulated by viral and bacterial RNA

BackgroundImmunoglobulin A nephropathy (IgAN) is the most frequent primary glomerulonephritis and the role of IL-6 in pathogenesis is becoming increasingly important. A recent whole genome DNA methylation screening in IgAN patients identified a hypermethylated region comprising the non-coding RNA Vault RNA 2–1 (VTRNA2–1) that could explain the high IL-6 levels. MethodsThe pathway leading to IL-6 secretion controlled by VTRNA2–1, PKR, and CREB was analyzed in peripheral blood mononuclear cells (PBMCs) isolated from healthy subjects (HS), IgAN patients, transplanted patients with or without IgAN. The role of double and single-strand RNA in controlling the pathway was investigated. ResultsVTRNA2–1 was downregulated in IgAN compared to HS and in transplanted IgAN patients (TP-IgAN) compared to non-IgAN transplanted (TP). The loss of the VTRNA2–1 natural restrain in IgAN patients caused PKR hyperphosphorylation, and consequently the activation of CREB by PKR, which, in turn, led to high IL-6 production, both in IgAN and in TP-IgAN patients. IL-6 levels could be decreased by the PKR inhibitor imoxin. In addition, PKR is normally activated by bacterial and viral RNA, and we found that both the RNA poly(I:C), and the COVID-19 RNA-vaccine stimulation significantly increased the IL-6 levels in PBMCs from HS but had an opposite effect in those from IgAN patients. ConclusionThe discovery of the upregulated VTRNA2–1/PKR/CREB/IL-6 pathway in IgAN patients may provide a novel approach to treating the disease and may be useful for the development of precision nephrology and personalized therapy by checking the VTRNA2–1 methylation level in IgAN patients.

The Role of IL-17 in the Pathogenesis of Oral Squamous Cell Carcinoma.

Elucidating the inflammatory mechanisms underlying formation and progression of oral squamous cell carcinoma (OSCC) is crucial for discovering new targeted therapeutics. The proinflammatory cytokine IL-17 has proven roles in tumor formation, growth, and metastasis. The presence of IL-17 is demonstrated in both in vitro and in vivo models, and in OSCC patients, is mostly accompanied by enhanced proliferation and invasiveness of cancer cells. Here we review the known facts regarding the role of IL-17 in OSCC pathogenesis, namely the IL-17 mediated production of proinflammatory mediators that mobilize and activate myeloid cells with suppressive and proangiogenic activities and proliferative signals that directly induce proliferation of cancer cells and stem cells. The possibility of a potential IL-17 blockade in OSCC therapy is also discussed.

The role of IL-6 in pathogenesis of abdominal aortic aneurysm in mice.

Although the pathogenesis of abdominal aortic aneurysm (AAA) remains unclear, evidence is accumulating to support a central role for inflammation. Inflammatory responses are coordinated by various soluble cytokines of which IL-6 is one of the major proinflammatory cytokines. In this study we examined the role of IL-6 in the pathogenesis of experimental AAA induced by a periaortic exposure to CaCl2 in mice. We now report that the administration of MR16-1, a neutralizing monoclonal antibody specific for the mouse IL-6 receptor, mildly suppressed the development of AAA. The inhibition of IL-6 signaling provoked by MR16-1 also resulted in a suppression of Stat3 activity. Conversely, no significant changes in either NFκB activity, Jnk activity or the expression of matrix metalloproteinases (Mmp) -2 and -9 were identified. Transcriptome analyses revealed that MR16-1-sensitive genes encode chemokines and their receptors, as well as factors that regulate vascular permeability and cell migration. Imaging cytometric analyses then consistently demonstrated reduced cellular infiltration for MR16-1-treated AAA. These results suggest that IL-6 plays an important but limited role in AAA pathogenesis, and primarily regulates cell migration and infiltration. These data would also suggest that IL-6 activity may play an important role in scenarios of continuous cellular infiltration, possibly including human AAA.

IL‐17 producing T cells correlate with polysensitization but not with bronchial hyperresponsiveness in patients with allergic rhinitis

BackgroundTh2-type T cell response has a considerable role in atopic diseases. The involvement of Th17 and IL-17 in atopy process provided new understanding of allergic diseases. Bronchial hyperresponsiveness is quite common in allergic rhinitis. We aimed to explore the expression of IL-17 producing CD3+ CD4+ T cells in peripheral blood of rhinitic patients, with/without bronchial hyperresponsiveness and sensitized to common allergens, as this relationship has not been examined.MethodsSixty one patients with allergic rhinitis and thirty controls were examined. IL-17 producing T cells were detected by flow cytometry, IL-17, IL-4 and IL-13 levels in peripheral blood were evaluated by ELISA. Bronchial hyperresponsiveness was investigated with methacholine challenge test. Atopy was evaluated by skin prick tests with common allergens.ResultsIL-17 producing T cell percentage of AR group was significantly higher: 2.59 ± 1.32 than in controls 1.24 ± 0.22, (p = 0.001). Significant sex related difference in CD3+ CD4+ IL-17 T cells was observed: respectively in male patients versus female 3.15 ± 1.8% and 2.31 ± 0.9%, (p = 0.02). Rhinitics had greater bronchodilator responses compared to controls (p = 0.001), however the percentages of T cells in both groups appeared equal. Serum IL-17 levels in AR group were significantly higher (5.10 ± 4.40) pg/ml than in controls (3.46 ±1.28) pg/ml, (p = 0.04). IL-4 levels (0.88 ± 1.27) and IL-13 levels (3.14 ± 5.85) in patients were significantly higher than in control’s (0.54 ± 0.10) pg/ml, (p = 0.001) and (1.19 ± 0.64) pg/ml; (p = 0.001) respectively.The percentages of T cells in patients sensitized to 5 allergens (group I) were significantly lower (1.91 ± 0.62) than those sensitized to more than 5 allergens (group II) (2.91 ± 1.5) (p = 0.004).ConclusionsThe observed higher levels of IL-17 producing T cells in polysensitized males suggest a role of IL-17 in pathogenesis of AR. The higher airway responsiveness in AR may not be Th17 dependent. The higher serum values of IL-17, IL-4 and IL-13 demonstrate the presence of cytokine balance in atopic diseases.

Multicentric Castleman’s Disease: A Challenging Diagnosis

Multicentric Castleman's disease (MCD) is a sytemic disorder with flares of non-specific symptoms suggestive of a chronic inflammatory syndrome. It is typically accompanied by generalized lymphadenopathy and multiorgan involvement. Histologically, two main variants of Castleman's disease exist, the hyalin vascular type and the plasma cell variant. Upon localization unicentric (localized), and multicentric (diffuse, systemic) subtypes can be distinguished with more different disease outcomes. Patients often exhibit acute phase reactions and several autoimmune phenomena, and are at high risk for developing malignancies. Both the idiopathic and the HHV-8-driven infectious forms of MCD represent distinct disease entities with a less favorable prognosis. The induction of human IL-6 excess via yet unknown upstream mechanisms, and overexpression of viral IL-6 by HHV-8 can pivotally influence MCD biology. Based on the role of IL-6 in pathogenesis, MCD is also designated as IL-6 lymphadenopathy. To date there are no direct therapeutic evidences, but having been translated to daily practice the main regulatory factors may serve as promising therapeutic targets.

The role of IL-17 in modulation of antitumour immunity and progression of colitis-associated cancer

Colorectal carcinoma is one of the most frequent malignancies worldwide. There is a strong belief that it is initiated in the inflammatory bowel disease microenvironment. Pro-inflammatory cytokines produced by malignant cells as well as by tumor infiltrating leukocytes facilitate origination, growth and progression of cancer. An important role of T cells in antitumor immunity is well established. CD4+ Th lymphocytes can be classified into a few functional phenotypes: T helper 1 (Th1), T helper 2 (Th2), T helper 17 (Th17), according to the ability to secrete different cytokines. Th1 lymphocytes play important role in induction of cellular immunity, while Th2 lymphocytes suppress cellular immunity and enhance humoral immune response. Th17 lymphocytes are the key players in inducing inflammation by recruitment of neutrophils and macrophages. The polarization of T-mediated immune response has multiple effects on tumor progression. Although Th2-type cytokines can induce acute tumor rejection, Th1- type cytokines provide a greater antitumor effect and can promote durable anti-tumor CD8+T cell response. However, the role of IL-17 in pathogenesis of colitis-associated cancer (CAC) has not been fully understood. The aim of this paper is to clarify the role of IL-17 in modulation of antitumor immunity and progression of colorectal carcinoma.

IL-17 Level in Patients with Dengue Virus Infection & its Association with Severity of Illness

Clinical symptoms of Dengue vary from mild febrile illness to severe infection. A potent pro-inflammatory cytokine, IL-17, secreted by mainly Th17 cells mediate inflammation and autoimmune diseases. Role of IL-17 in pathogenesis of dengue virus (DV) infection is not clear. Total 211 dengue patients and 70 healthy controls were enrolled. IL-17 level was tested in serum samples from all cases and controls. Cases were grouped as either dengue or severe dengue; based on WHO (2009) classification. Anti DV IgG antibody detection and DV serotype specific PCR were also done. Levels of IL-17 in dengue and severe dengue patients, primary and secondary DV infection were compared. Association of DV serotypes with severity of illness and various clinical and laboratory features with IL-17 levels were analyzed. Of total 211cases, 90 and 121cases were presenting as dengue and severe dengue illness, respectively. Levels of IL-17 were significantly higher in dengue patients as compared to control. Mean level of IL-17 was higher in severe cases than non severe cases; however difference was not statistically significant. Stratified analysis of IL-17 level in different age group showed significantly high IL-17 levels in children with severe dengue. Mean level of IL-17 was also significantly higher in cases with secondary DV infection in comparison to primary DV infection. Levels of IL-17 were higher in patients with DV-2 infection in comparison to cases with DV-1 and DV-3 infection. Significant positive association of high IL-17 levels was seen with pleural effusion and respiratory distress. IL-17 appears to be associated with severe DV infection. It is very important to understand the exact role of IL-17 in the pathogenesis of severe DV infection.