Interleukin‑27 ameliorates allergic asthma by alleviating the lung Th2 inflammatory environment
Jiameng LuXiaoqing JiLixia WangFei SunChuanjun HuangHaiying PengYunxiu JiangZihan GuoXinyi LiuYanbo JiDegan Lu
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Abstract:
Interleukin (IL)‑27 can inhibit the differentiation of Th2 cells and plays a role in the development of asthma. However, whether the therapeutic administration of IL‑27 in a mouse model of asthma can inhibit allergic responses remains a matter of debate. Additionally, the mechanisms through which IL‑27 ameliorates inflammatory responses in asthma are not yet fully understood. Thus, the aim of the present study was to examine the effects of IL‑27 on asthma using a mouse model and to elucidate the underlying mechanisms. For this purpose, mice received an intranasal administration of IL‑27 and the total and differential cell counts, levels of cytokines and type 1 regulatory T (Tr1) cells in the lungs were detected. The protein and mRNA levels of signal transducer and activator of transcription (STAT)1 and STAT3 were analyzed and airway remodeling was assessed. The results indicated that IL‑27 did not ameliorate airway inflammation, airway hyperresponsiveness, and airway remolding when administrated therapeutically. Preventatively, the administration of IL‑27 decreased the concentrations of Th2 cytokines and increased the number of Tr1 cells. The protein and mRNA levels of STAT1 and STAT3 were increased. Taken together, these findings demonstrate that the prophylactic administration of IL‑27 ameliorates asthma by alleviating the lung Th2 inflammatory environment through the restoration of both the STAT1 and STAT3 pathways. IL‑27 may thus prove to be useful as a novel agent for the prevention of asthma.Keywords:
STAT1
The signal transducers and activators of transcription (STAT)1 and STAT3 genes are specifically activated by phosphorylated STATs 1 and 3, respectively, resulting in large and prolonged increases in the levels of unphosphorylated STATs (U-STATs) in response to interferons (for STAT1) or ligands that activate gp130, such as IL-6 (for STAT3). U-STATs 1 and 3 are transcription factors that drive gene expression by mechanisms distinct from those used by phosphorylated STATs. U-STAT3 drives expression of many proteins not induced by phospho-STAT3, including several that are important in tumorigenesis. U-STAT1 prolongs and increases expression of a subset of proteins induced initially in response to phospho-STAT1, leading to antiviral and immune responses that are long-lived. U-STAT1 levels are also high in some cancers, and the protein products of genes induced by U-STAT1 enhance resistance to DNA damage. Therefore, interferons not only drive short-term expression of proteins that inhibit growth and promote apoptosis and immune surveillance, but also promote long-term expression of proteins that facilitate tumor survival.
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Signal Transducer and Activator of Transcription (STAT) pathway is connected upstream with Janus kinases (JAK) family protein and capable of integrating inputs from different signaling pathways. Each family member plays unique functions in signal transduction and crucial in mediating cellular responses to different kind of cytokines. STAT family members notably STAT3 and STAT5 have been implicated in cancer progression whereas STAT1 plays opposite role by suppressing tumor growth. Persistent STAT3/5 activation is known to promote chronic inflammation, which increases susceptibility of healthy cells to carcinogenesis. Here, we review the role of STATs in cancers and inflammation while discussing current therapeutic implications in different cancers and test models, especially the delivery of STAT3/5 targeting siRNA using nanoparticulate delivery system.
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The family of signal transducer and activator of transcription (STAT) factors play a critical role in the signaling of many cytokines. In addition to the involvement of STAT6 in allergic bronchial asthma, both STAT1 and STAT3 have also been implicated. However, there is little information whether or not the T helper 2 cytokines, which cause several key features of allergic asthma, really induce the activation of STAT1 and/or STAT3 in bronchial smooth muscle (BSM) cells. In the present study, the effects of interleukin-13 (IL-13) and IL-4 on activation of these STAT molecules were examined in cultured human bronchial smooth muscle cells (hBSMCs). After a starvation period, the hBSMCs were treated with 100 ng/ml of IL-13 or IL-4. Total protein samples were prepared at intervals of 1, 3, 6, 12 and 24 hours after the cytokine treatment, and Western blot analyses for total and tyrosine-phosphorylated STATs molecules were conducted. As a result, ut was found that both IL-13 and IL-4 caused a significant increase in the levels of phosphorylated STAT1. Examination of the time-course revealed a peak of STAT1 phosphorylation at 1 hr after cytokine application. In contrast, neither IL-13 nor IL-4 induced phosphorylation of STAT3. Neither of these cytokines changed the protein expression of the STATs themselves. These findings suggest that STAT1, but not STAT3, might also be one of the crucial signal transducers in the development of BSM hyper-responsiveness, which is one of the causes of AHR in asthmatics.
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The signal transducer and activator of transcription–3 (Stat3) protein is activated by the interleukin 6 (IL-6) family of cytokines, epidermal growth factor, and leptin. A protein named PIAS3 (protein inhibitor of activated STAT) that binds to Stat3 was isolated and characterized. The association of PIAS3 with Stat3 in vivo was only observed in cells stimulated with ligands that cause the activation of Stat3. PIAS3 blocked the DNA-binding activity of Stat3 and inhibited Stat3-mediated gene activation. Although Stat1 is also phosphorylated in response to IL-6, PIAS3 did not interact with Stat1 or affect its DNA-binding or transcriptional activity. The results indicate that PIAS3 is a specific inhibitor of Stat3.
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In most cells studied so far, interferon‐α (IFN‐α) activates signal transducer and activator of transcription (Stat1), Stat2 and Stat3, whereas interferon‐γ (IFN‐γ) induces Stat1 only. In general, each of the several dozens of cytokines, growth factors and hormones that signal through the Janus kinases‐signal transducers and activators of transcription (Jak‐STAT) pathway activates a distinct subset of STATs, and this selectivity is thought to be essential for the specificity of the cellular responses toward these ligands. Here, we have studied the pattern of STAT activation in the human lymphoblastoid cell line Daudi in response to IFN‐α. In addition to Stat1, Stat2 and Stat3 activation, IFN‐α was found to directly induce activation of Stat5 and Stat6. Cell‐type‐specific activation of additional STATs could be responsible for cell‐type‐specific responses to IFN‐α.
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3049 Signal transducer and activator of transcription factor (STAT) family proteins are latent cytoplasmic transcription factors that convey signals from cytokine and growth factor receptors to nucleus. We studied about STAT1 and STAT3 among STAT families. The two act pretty differently in cancer cell. STAT1 is associated with apoptosis pathway while STAT3 is tumorigenecity. To investigate a primary role of STAT3 we blocked STAT3 by two Jak kinase inhibitors AG490 (Jak2-STAT3 pathway inhibition) and Jak kinase total inhibitor. First, when we tried to inhibit STAT3 using AG490, significant cell growth arrest was identified. But in case of JAK total inhibitor, there was no cell growth retardation. So we concerned about STAT1 action, which one of the reason why cell growth has no influence after treatment of JAK total inhibitor. To confirm this, we used small interfering RNA of STAT1. In head and neck cancer, suppression of STAT1 by si-RNA resulted in cell growth increasing. Furthermore, the growth inhibitory effect of AG490 was reduced by treatment with si-RNA of STAT1. Also, we observed up-regulation of p-STAT1 by several anti-cancer drugs and identified involvement of STAT1 activation in growth-inhibitory by anti-cancer drugs. In conclusion, tumor killing effect induced by STAT3 inhibition is related with STAT1 action. Thus, when STAT1 is missing, cell death efficiency is decreasing, even though STAT3 is blocked. To improve tumor killing effect in HNSCC, it should be considered not only STAT3 inhibition but also STAT1 activation.
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Objective Signal transducer and activator of transcription 1α(STAT1α) is essential to IFN γ and IFN α regulated gene expression, while STAT1β, an alternate splice form mediates only IFN α dependent gene expression. STAT3α and STAT3β splice forms are also differentially activated in response to cytokines including IL 6, IL 10 and GM CSF. In this report, we studied the host immune response to viral infection with a murine hepatitis model for rates of STAT1α, β and STAT3α, β activation following infection with hepatitis virus in resistant and sensitive mouse strains. Methods Mice were i.p infected with 100 PFU of MHV 3. The mice were killed at required intervals and livers/spleens were immediately frozen in liquid nitrogen. Nuclear extracts were separated in an 8% SDS polyacrylamide gel and proteins were detected by immunoblotting. DNA mobility shift assay was also performed to examine the protein DNA interreaction. Results STAT1 and STAT3 activation in spleen enhanced in 24 hs to 72 hs following MHV 3 infections in both sensitive and resistant mouse strains. However, beyond this time period, ratio of activated α to β splice form for STAT1 and STAT3 enhanced to above 1.0 in resistant A/J mice, while decreased to less than 0.3 in MHV 3 sensitive BALB/c and C3H/HeJ strains. Activated STAT1α/β and STAT3α/β ratio in liver was similar in both resistant and sensitive mouse strains. Conclusion The ratios of activated STAT1α/β and STAT3α/β in mixed leukocytes from spleen predict outcome of MHV 3 infection and may function as an important markers of therapeutic effect for modification of host immune response
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