Th17/IL-17A axis is critical for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc): SSc patients with high levels of serum IL-17A exhibit reduced lung functions and increased prevalence of PAH.

BACKGROUND: It is thought that systemic sclerosis (SSc) might be a T helper 17 (Th17) cell-driven autoimmune disease. Noticeably, pulmonary arterial hypertension (PAH) is a leading cause of death in patients with SSc. Here, we investigated the association between serum Th17-related cytokines and prevalence of PAH in SSc patients. METHODS: This study included 72 SSc patients and 51 healthy controls (HC). We determined clinical manifestations, immunophenotypes including Th subsets in peripheral blood lymphocytes, and the serum levels of interleukin (IL)-17A, IL-17A/F, IL-17B. IL-17C, IL-17D. IL-1ß, IL-6, IL-21, IL-22, and IL-23. RESULTS: The frequency of Th17 cells was significantly increased in SSc patients compared to HC and was positively correlated with the modified Rodnan skin scores. Furthermore, the serum levels of IL-17A, IL-17D, IL-1ß, and IL-6 were significantly increased in SSc patients compared to HC. SSc patients with detected IL-17A showed high levels of IL-17A/F, IL-1ß, IL-6, and IL-22, and high frequency of Th17 cells. Interestingly, these patients exhibited the reduced lung functions and increased prevalence of PAH significantly compared to patients with undetected IL-17A. Similarly, SSc patients with detected IL-17A and high IL-6 (≥1.2 pg/mL) exhibited the decreased lung functions and increased prevalence of PAH compared to patients with undetected IL-17A and low IL-6. CONCLUSION: We found that SSc patients with high levels of serum IL-17A or both IL-17A and IL-6 show reduced lung functions and high prevalence of PAH. Consequently, it is highly probable that Th17/IL-17A axis is critical for the prevalence of PAH in SSc patients.

Th17/IL-17 Axis in HTLV-1-Associated Myelopathy Tropical Spastic Paraparesis and Multiple Sclerosis: Novel Insights into the Immunity During HAMTSP.

Human T lymphotropic virus-associated myelopathy/tropical spastic paraparesis (HTLV/TSP), also known as HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and multiple sclerosis (MS) are chronic debilitating diseases of the central nervous system; although the etiology of which is different, similarities have been observed between these two demyelinating diseases, especially in clinical manifestation and immunopathogenesis. Exorbitant response of the immune system to the virus and neurons in CNS is the causative agent of HAM/TSP and MS, respectively. Helper T lymphocyte-17 cells (Th17s), a component of the immune system, which have a proven role in immunity and autoimmunity, mediate protection against bacterial/fungal infections. The role of these cells has been reviewed in several CNS diseases. A pivotal role for Th17s is presented in demyelination, even more axial than Th1s, during MS. The effect of Th17s is not well determined in HTLV-1-associated infections; however, the evidence that we have supplied in this review illustrates the attendance, also the role of Th17 cells during HAM/TSP. Furthermore, for better conception concerning the trace of these cells in HAM/TSP, a comparative characterization with MS, the resembling disease, has been applied here.

A Pro-Inflammatory Signature Constitutively Activated in Monogenic Autoinflammatory Diseases.

Autoinflammatory diseases (AIDs) are disorders characterised by recurrent inflammatory episodes in charge of different organs with no apparent involvement of autoantibodies or antigen-specific T lymphocytes. Few common clinical features have been identified among all monogenic AIDs (mAIDs), while the search for a common molecular pattern is still ongoing. The aim of this study was to increase knowledge on the inflammatory pathways in the development of mAIDs in order to identify possible predictive or diagnostic biomarkers for each disease and to develop future preventive and therapeutic strategies. Using protein array-based systems, we evaluated two signalling pathways known to be involved in inflammation and a wide range of inflammatory mediators (pro-inflammatory cytokines and chemokines) in a cohort of 23 patients affected by different mAIDs, as FMF, TRAPS, MKD, Blau syndrome (BS), and NLRP12D. Overall, we observed upregulation of multiple signalling pathway intermediates at protein levels in mAIDs patients' PBMCs, compared with healthy controls, with significant differences also between patients. FMF, TRAPS, and BS presented also peculiar activations of inflammatory pathways that can distinguish them. MAPK pathway activation, however, seems to be a common feature. The serum level of cytokines and chemokines produced clear differences between patients with distinct diseases, which can help distinguish each autoinflammatory disease. The FMF cytokine production profile appears broader than that of TRAPS, which, in turn, has higher cytokine levels than BS. Our findings suggest an ongoing subclinical inflammation related to the abnormal and constitutive signalling pathways and define an elevated inflammatory cytokine signature. Moreover, the upregulation of Th17-related cytokines emphasises the important role for Th17 and/or Th17-like cells also in monogenic AIDs.

Th17-Related Cytokines as Potential Discriminatory Markers between Neuromyelitis Optica (Devic's Disease) and Multiple Sclerosis-A Review.

Multiple sclerosis (MS) and Devic's disease (NMO; neuromyelitis optica) are autoimmune, inflammatory diseases of the central nervous system (CNS), the etiology of which remains unclear. It is a serious limitation in the treatment of these diseases. The resemblance of the clinical pictures of these two conditions generates a partial possibility of introducing similar treatment, but on the other hand, a high risk of misdiagnosis. Therefore, a better understanding and comparative characterization of the immunopathogenic mechanisms of each of these diseases are essential to improve their discriminatory diagnosis and more effective treatment. In this review, special attention is given to Th17 cells and Th17-related cytokines in the context of their potential usefulness as discriminatory markers for MS and NMO. The discussed results emphasize the role of Th17 immune response in both MS and NMO pathogenesis, which, however, cannot be considered without taking into account the broader perspective of immune response mechanisms.

Based on G-Series Mouse TH17 Array Study the Effect of Fluoride on C2C12 Cells Cytokines Expression.

C2C12 cells were cultured on medium containing fluoride (0, 1, and 2.5 mmol/L) for 48 h to investigate the effect of excessive fluoride on T helper 17 (Th17)-related cytokine expression profile in skeletal muscle cells, and the culture supernatant was collected and subjected for the detection of 18 cytokines via Th17 array. Results showed that compared with the control group, no differential expression proteins (DEPs) were found in the 1 mmol/L fluoride group; however, eight DEPs were upregulated in the 2.5 mmol/L fluoride group, including macrophage inflammatory protein-3α (MIP-3α), interleukin-21 (IL-21), IL-13, IL-17F, IL-28A, transforming growth factor type beta 1 (TGF-ß1), IL-23, and IL-17A. In addition, five DEPs (MIP-3α, IL-13, IL-21, TGF-ß1, and IL-17F) were upregulated in the 2.5 mmol/L fluoride group compared with the 1 mmol/L fluoride group. Gene ontology analysis revealed that the positive regulation of cytokine production, cytokine activity, receptor ligand activity, and cytokine receptor binding accounted for high percent of DEPs present. Kyoto Encyclopedia of Genes and Genomes analysis showed that these DEPs primarily involved 12 pathways enriched in the cytokine-cytokine receptor interaction and IL-17 signaling pathway after 2.5 mmol/L fluoride treatment. The results indicated that fluoride might induce cytotoxicity by disturbing Th17-related cytokine expression.

Ability of two new thiazolidinediones to downregulate proinflammatory cytokines in peripheral blood mononuclear cells from children with asthma

Allergic asthma is a chronic, complex inflammatory disease of the airway. Despite extensive studies on the immunomodulation of T helper (Th) cell pathways (i.e., Th1 and Th2) in asthma, little is known about the effects of Th17 pathway modulation, particularly that involving peroxisome proliferator-activated receptors (PPARs). In response, two new thiazolidinedione derivatives-namely, LPSF-GQ-147 and LPSF-CR-35 were synthesized and evaluated for their immunomodulatory effects on Th17-related cytokines, including interferon γ (IFNγ), interleukin IL-6, IL-17, and IL-22 in the peripheral blood mononuclear cells of asthmatic children. Both compounds were nontoxic even at high concentrations (i.e., 100 µM). The LPSF-CR-35 compound significantly reduced the levels of IL-17A (p = .039) and IFNγ (p = .032) at 10 µM. For IL-22 and IL-6, significant reduction occurred at 100 µM (p = .039 and p = .02, respectively). Conversely, LPSF-GQ-147 did not significantly inhibit the production of the tested cytokines, the levels of all of which were more efficiently reduced by LPSF-CR-35 than methylprednisolone, the standard compound. Real-time polymerase chain reaction assay confirmed that LPSF-GQ-147 has significant PPARγ modulatory activity. Such data indicate that both LPSF-CR-35 and LPSF-GQ-147 are promising candidates as drugs for treating inflammation and asthma

A possible association of baseline serum IL-17A concentrations with progression-free survival of metastatic colorectal cancer patients treated with a bevacizumab-based regimen.

BACKGROUND: Colorectal cancer is a major public health issue worldwide. Interleukin-17 (IL-17) and Th17 (T-helper cell type 17)-related molecules are involved in tumor development and in resistance to bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody used in association with chemotherapy in metastatic colorectal cancer. Some studies have previously shown that IL-17A and IL-17F polymorphisms, respectively rs2275913 and rs763780, are associated with gastric or colorectal cancer risk. Here we aimed at studying the influence of IL-17A-related individual factors on overall survival and progression-free survival in patients with metastatic colorectal cancer treated with a bevacizumab-based chemotherapy. METHODS: Pre-treatment serum biomarkers were retrospectively evaluated in 122 metastatic colorectal cancer patients treated by bevacizumab in combination with chemotherapy at 2-weeks intervals in a prospective cohort study (NCT00489697). The polymorphisms of IL-17A and IL-17F were analyzed by polymerase chain reaction - restriction fragment length polymorphism. Serum concentrations of Th17-related cytokines were measured by MultiPlex. The impact of individual parameters on overall survival and progression-free survival was assessed using multivariate Cox models. RESULTS: High baseline IL-17A serum concentrations were significantly associated with shorter progression-free survival [p = 0.043]. Other baseline serum Th17-related cytokines and polymorphisms of IL-17 were not associated with overall survival or progression-free survival. CONCLUSIONS: In this ancillary study, baseline serum IL-17A concentration is the only Th17/IL-17 related factor that was significantly associated with the response of patients with metastatic colorectal cancer to bevacizumab. But this main significant result is highly dependent on one case which, if left out, weakens the data. Other clinical studies are required to confirm this association. TRIAL REGISTRATION: NCT00489697 . June 20, 2007.

Th17/Treg-related cytokine imbalance in sulfur mustard exposed and stable chronic obstructive pulmonary (COPD) patients: correlation with disease activity.

In this study, we investigated expression changes of Th17/Treg-related cytokine in transbronchial lung biopsy (TBLBs) of sulfur mustard (SM) exposure, stable chronic obstructive pulmonary disease (COPD) patients and also compared it with a healthy control (HC) group. Here, ROR-γt, FoxP3, and Treg/Th17-related cytokines (IL-10, IL-17A, IL-6, and TGF-ß1) were assessed using a combination of RT-QPCR and ELISA in 11 SM-exposed cases, 9 patients with GOLD stage II COPD diagnosed, and 8 HC. Our results showed that the levels of Foxp3 expression were lower and ROR-γt expression was higher in SM and COPD patients when compared with HC (all p values were less than 0.001). The relative Foxp3 expressions and Foxp3/ROR-γt ratio were positively correlated with FEV1 (%) pred (R = 0.682 and R = 0.602, respectively; p ≤ 0.001). However, the relative ROR-γt expressions were inversely correlated with FEV1 (%) pred (R= -0.75, p = 0.003) and relative Foxp3 expression (R= -0.704, p = 0.003). The mRNA and protein expression of IL-10 were significantly decreased in SM and COPD patients compared with HC (p < 0.001). An increase of IL-17A (∼7.2 fold) and TGF-ß1 (∼5.6 fold) are involved in the lung exacerbation of SM and COPD patients. The expression of IL-6 was variable between three groups (p ≥ 0.05). In addition, an inverse correlation were observed between FEV1 (%) pred and expressions of IL-17A (R= -0.741), IL-6 (R= -0.673) and TGF-ß1 (R= -0.632) (p ≤ 0.001). Instead, positive correlation was found between IL-10 ratios and FEV1 (%) pred (R = 0.777, p = 0.001). These findings suggest that Treg/Th17-mediated distributions are involved in the progression of chronic lung injury of SM and COPD patients.

TIPE2 Play a Negative Role in TLR4-Mediated Autoimmune T Helper 17 Cell Responses in Patients with Myasthenia Gravis.

Th17-related cytokines have been suggested to play a crucial role in myasthenia gravis (MG) pathogenesis.The tumor necrosis factor (TNF)-α-induced protein 8-like-2 (TNFAIP8L2 or TIPE2), is a newly identified member of the tumor necrosis TNFAIP8 family which is an essential negative regulator of both innate and adaptive immunity. In the present study, the expression of TIPE2 mRNA and protein in peripheral blood mononuclear cells (PBMC) from healthy and MG subjects were detected by Real-time PCR and Western blotting.The serum IL-6, IL-17 and IL-21 levels were tested by ELISA. Furthermore, PBMC from MG patients were purified and stimulated with LPS (TLR4 agonist) with or without transfection of TIPE2 expressing adenovirus, then the expression of TIPE2 and Th17-specific transcriptional factor RORγt and the IL-6, IL-17 and IL-21 levels of supernatant were analized. Our data demonstrated that the expression of TIPE2 mRNA and protein was reduced in MG compared with normal controls, with lower expression in generalized patients than in ocular ones. Furthermore, TIPE2 mRNA presents a significantly negative correlation with the serum levels of IL-6, IL-17 and IL-21 in either generalized patients or ocular patients. In cultured MG PBMC, TLR4 activation led to the down-regulation of TIPE2, while the expression of RORγt and production of IL-6, IL-17 and IL-21 were significantly increased. However, when TIPE2 was overexpressed, these TLR4 activation-induced effects were significantly abrogated. Overall, our results indicated for the first time that TIPE2 may participate in the development of MG through negatively regulation of TLR4-mediated autoimmune T helper 17 cell responses.

Association between Th17-related cytokines and risk of non-small cell lung cancer among patients with or without chronic obstructive pulmonary disease.

BACKGROUND: CD4 (+) T helper 17 (Th17) cells play critical roles in inflammation and tumor development. The involvement of Th17 cells in chronic obstructive pulmonary disease (COPD)-type inflammation-associated lung cancer has also been confirmed in animal models. However, to the authors' knowledge, it is unknown whether the role of Th17 cells is different in patients with lung cancer complicated with COPD compared with those without COPD. In the current study, the authors attempted to determine the association between the circulating levels of Th17-related cytokines and the clinical characteristics of non-small cell lung cancer (NSCLC) in patients with or without COPD. METHODS: The authors designed a matched case-control study that included 70 patients with NSCLC with COPD, 148 patients with NSCLC without COPD, and 148 healthy controls. The data regarding the clinicopathological features of these participants were collected. Circulating levels of Th17-related cytokines, including interleukin (IL) 23 (IL-23), IL-17A, IL-17F, IL-22, and tumor necrosis factor-α, were measured. RESULTS: The circulating levels of IL-23, IL-17A, IL-17F, IL-22, and tumor necrosis factor-α were found to be significantly higher in the patients with NSCLC compared with the healthy controls (P<.05). The elevated levels were found to be significantly associated with lung cancer risk (P<.05). However, no significant differences were found between patients with NSCLC with COPD and patients without COPD. It is interesting to note that, among patients with NSCLC without COPD, the levels of these cytokines were consistently higher among patients with stage I to stage IIIA disease compared with those with stage IIIB to stage IV disease (P<.05). In addition, the 5 Th17-related cytokines demonstrated pairwise correlations, with Spearman rank correlation coefficients of 0.646 to 0.888 (P<.05). CONCLUSIONS: The results of the current study indicate a clear association between the Th17-related cytokine profile and the risk of NSCLC complicated by the presence or absence of COPD.

IL-17A, IL-22, and IL-23 as Markers of Psoriasis Activity: A Cross-sectional, Hospital-based Study.

INTRODUCTION: T-helper 1 (Th1), Th17 cells, and their related cytokines are implicated in psoriasis pathogenesis although the contribution of each group of cytokines in psoriasis activity has not been fully clarified. OBJECTIVES: To investigate whether Th17-related cytokines are associated with psoriasis activity. METHODS: The serum levels of interleukin (IL)-1ß, 6, 8, 17Α, 22, 23, and tumor necrosis factor-α (TNFα) were measured with flow cytometry in 35 patients with plaque psoriasis (21 with stable and 14 with active disease) and in 20 healthy controls. RESULTS: Interleukin-6, 8, 17A, 22, 23, and TNFα were significantly elevated in psoriasis patients compared with controls. In the sensitivity analyses, patients with active disease showed significantly increased levels of IL-17A, IL-23, and IL-22 as compared to the group of patients with stable psoriasis. CONCLUSIONS: Our study highlights a possible crucial role of IL-17A, IL-22, and IL-23 in the activity of psoriasis and the early stages of the disease.