IFN-b currently serves as one of the major treatments for MS. Its anti-inflammatory mechanism has been reported as involving a shift in cytokine balance from Th1 to Th2 in the T-cell response against elements of the myelin sheath. In addition to the Th1 and Th2 groups, two other important pro-inflammatory cytokines, IL-17 and osteopontin (OPN), are believed to play important roles in CNS inflammation in the pathogenesis of MS. In this study, we examined the potential effects of IFN-b on the regulation of OPN and IL-17 in MS patients. We found that IFN-b used in vitro at 0.5-3 ng/mL significantly inhibited the production of OPN in primary T cells derived from PBMC. The inhibition of OPN was determined to occur at the CD4 1 T-cell level. In addition, IFN-b inhibited the production of IL-17 and IL-21 in CD4 1 T cells. It has been described that IFN-b suppresses IL-17 production through the inhibition of a monocytic cytokine, the intracellular translational isoform of OPN. Our further investigation demonstrated that IFN-b also acted directly on the CD4 1 T cells to regulate OPN and IL-17 expression through the type I IFN receptor-mediated activation of STAT1 and suppression of STAT3 activity. Administration of IFN-b to EAE mice ameliorated the disease severity. Furthermore, spinal cord infiltration of OPN 1 and IL-17 1 cells decreased in IFN-b-treated EAE mice along with decreases in serum levels of OPN and IL-21. Importantly, decreased OPN production by IFN-b treatment contributes to the reduced migratory activity of T cells. Taken together, the results from both in vitro and in vivo experiments indicate that IFN-b treatment can down-regulate the OPN and IL-17 production in MS. This study provides new insights into the mechanism of action of IFN-b in the treatment of MS. IntroductionMS is a disease of the CNS characterized by chronic inflammatory and demyelinating processes [1]. CNS inflammation is considered as an important feature in MS pathology, and is directly associated with the disease process in MS [2]. Agents that have anti-inflammatory properties have been shown to suppress the disease activity to various degrees. MS is now commonly treated with an immunomodulatory agent, IFN-b, which has shown significant treatment efficacy and is à These authors contributed equally to the work. Eur. J. Immunol. 2009. 39: 2525-2536 Immunomodulation 2525 thought to involve a number of different mechanisms of action [3,4]. However, despite extensive clinical experience in the use of IFN-b, its mechanism of action has not been fully elucidated. Studies into its mechanism of action have revealed that anti-inflammatory properties of IFN-b function through the regulation of Th1 and Th2 cytokines [5,6]. Further, there is an evidence indicating that IFN-b promotes the production of IL-10 and inhibits the action of pro-inflammatory cytokines [7,8].Osteopontin (OPN), also known as early T lymphocyte activation-1, has been recently recognized as a pro-inflammatory cytokine promoting the production of IFN-g and IL-12 in macrophages...

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MBP-specific autoreactive T cells are considered pro-inflammatory T cells and thought to play an important role in the pathogenesis of multiple sclerosis (MS). Here, we report that MBP(83-99)-specific T cells generated from MS patients (n = 7) were comprised of pro-inflammatory and regulatory subsets of distinct phenotypes. The pro-inflammatory phenotype was characterized by high production of IFN-gamma, IL-6, IL-21 and IL-17 and low expression of FOXP3, whereas the regulatory subset expressed high levels of FOXP3 and exhibited potent regulatory functions. The regulatory subset of MBP-specific T cells appeared to expand from the CD4(+)CD25(-) T-cell pool. Their FOXP3 expression was stable, independent of the activation state and it correlated with suppressive function and inversely with the production of IFN-gamma, IL-6, IL-21 and IL-17. In contrast, the phenotype and function of FOXP3(low) MBP-specific T cells were adaptive and dependent on IL-6. The higher frequency of FOXP3(high) MBP-specific T cells was observed when IL-6 was neutralized in the culture of PBMC with MBP. The study provides new evidence that MBP-specific T cells are susceptible to pro-inflammatory cytokine milieu and act as either pro-inflammatory or regulatory T cells.

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Objective: To explore the clinicopathological impact of lncRNAs, immunotherapy, and DNA methylation in lung squamous cell carcinoma (LUSC), emphasizing their exact roles in carcinogenesis and modes of action.Background: LUSC is the second most prevalent form, accounting for around 30% of non-small cell lung cancer (NSCLC). To date, molecular-targeted treatments have significantly improved overall survival in lung adenocarcinoma patients but have had little effect on LUSC therapy. As a result, there is an urgent need to discover new treatments for LUSC that are based on existing genomic methods. Methods:In this review, we summarized and analyzed recent research on the biological activities and processes of lncRNA, immunotherapy, and DNA methylation in the formation of LUSC. The relevant studies were retrieved using a thorough search of Pubmed, Web of Science, Science Direct, Google Scholar, and the university's online library, among other sources.Conclusions: LncRNAs are the primary components of the mammalian transcriptome and are emerging as master regulators of a number of cellular processes, including the cell cycle, differentiation, apoptosis, and growth, and are implicated in the pathogenesis of a variety of cancers, including LUSC. Understanding their role in LUSC in detail may help develop innovative treatment methods and tactics for LUSC. Meanwhile, immunotherapy has transformed the LUSC treatment and is now considered the new standard of care. To get a better knowledge of LUSC biology, it is critical to develop superior modeling systems. Preclinical models, particularly those that resemble human illness by preserving the tumor immune environment, are essential for studying cancer progression and evaluating novel treatment targets. DNA methylation, similarly, is a component of epigenetic alterations that regulate cellular function and contribute to cancer development.By methylating the promoter regions of tumor suppressor genes, abnormal DNA methylation silences their expression. DNA methylation indicators are critical in the early detection of lung cancer, predicting therapy efficacy, and tracking treatment resistance. As such, this review seeks to explore the clinicopathological impact of lncRNAs, immunotherapy, and DNA methylation in LUSC, emphasizing their exact roles in carcinogenesis and modes of action.