Transfer of type-1 helper T-conditioned (Th1-conditioned) cells promotes functional recovery with enhanced axonal remodeling after spinal cord injury (SCI). This study explored the molecular ...mechanisms underlying the beneficial effects of pro-inflammatory Th1-conditioned cells after SCI. The effect of Th1-conditioned cells from interferon-γ (ifn-γ) knockout mice (ifn-γ(-/-) Th1 cells) on the recovery after SCI was reduced. Transfer of Th1-conditioned cells led to the activation of microglia (MG) and macrophages (MΦs), with interleukin 10 (IL-10) upregulation. This upregulation of IL-10 was reduced when ifn-γ(-/-) Th1 cells were transferred. Intrathecal neutralization of IL-10 in the spinal cord attenuated the effects of Th1-conditioned cells. Further, IL-10 is robustly secreted from Th1-conditioned cells in an ifn-γ-dependent manner. Th1-conditioned cells from interleukin 10 knockout (il-10(-/-)) mice had no effects on recovery from SCI. These findings demonstrate that ifn-γ-dependent secretion of IL-10 from Th1 cells, as well as native MG/MΦs, is required for the promotion of motor recovery after SCI.
The role of T lymphocytes in central nervous system (CNS) injuries is controversial, with inconsistent results reported concerning the effects of T-lymphocyte transfer on spinal cord injury (SCI). ...Here, we demonstrate that a specific T-lymphocyte subset enhances functional recovery after contusion SCI in mice. Intraperitoneal adoptive transfer of type 1 helper T (Th1)-conditioned cells 4 days after SCI promoted recovery of locomotor activity and tactile sensation and concomitantly induced regrowth of corticospinal tract and serotonergic fibers. However, neither type 2 helper T (Th2)- nor IL-17-producing helper T (Th17)-conditioned cells had such effects. Activation of microglia and macrophages were observed in the spinal cords of Th1-transfered mice after SCI. Specifically, M2 subtype of microglia/macrophages was upregulated after Th1 cell transfer. Neutralization of interleukin 10 secreted by Th1-conditioned cells significantly attenuated the beneficial effects by Th1-conditioned lymphocytes after SCI. We also found that Th1-conditioned lymphocytes secreted significantly higher levels of neurotrophic factor, neurotrophin 3 (NT-3), than Th2- or Th17-conditioned cells. Thus, adoptive transfer of pro-inflammatory Th1-conditioned cells has neuroprotective effects after SCI, with prospective implications in immunomodulatory treatment of CNS injury.
An abstract of a study by Sugase et al aiming to evaluate the antitumor effect of SOCS-1 gene therapy using adenoviral vector (AdSOCS-1) as monotherapy and combination therapy with radiation is ...presented. The results indicated that overexpression of SOCS-1 in monotherapy and combination therapy with radiation inhibited the progression of esophageal squamous cell carcinoma in vitro.
An abstract of a study by Wada et al aiming to detecting secondary C-KIT mutations in the peripheral blood of patients with imatinib-resistant gastrointestinal stromal tumor is presented. Secondary ...C-KIT mutations could be detected in circulating tumor DNA (ctDNA) from peripheral blood samples. Contrary to cfDNA concentration, the fraction of ctDNA changed along with tumor status.
Therapeutic effects of green tea involve an inhibitory function of its constituent polyphenol epigallocatechin gallate (EGCG) on cell signaling. The specificity and mechanism(s) by which EGCG ...inhibits cell signaling have remained unclear. Here, we demonstrate that green tea and EGCG induce suppressor of cytokine signaling 1 (SOCS1) gene expression, a negative regulator of specific cell signaling pathways. In mouse immune cells, EGCG induces SOCS1 expression via an oxidative (superoxide) pathway and activation of the signal transducer and activator of transcription 5 transcription factor. EGCG inhibited SOCS1-regulated cell signaling, but this inhibitory effect was abrogated in cells deficient in SOCS1. These findings identify a mechanism by which EGCG inhibits cell signaling with specificity, mediated by induction of the negative regulator SOCS1.
Cold is one of several important pathogenic factors in conditions such as livedo reticularis with winter ulceration (LRWU) 1, cold urticaria 2,3. As yet however, the effects resulting from cold ...stimulation remain poorly understood.
In the present study, using DNA microarray analysis, we investigated gene expression profiles in cultured human normal dermal microvascular endothelial cells (dHMVECs) exposed to different temperatures (10, 20 and 37°C). Quantitative real-time polymerase chain reaction (qPCR) was used to confirm gene expression results obtained from DNA microarray. ELISA assay was used to evaluate protein expression in culture medium of dHMVECs, mice and patients’ sera.
By DNA microarray analysis, differential transcriptional expressions of 137 genes were identified compared to 37°C. 21 genes were both regulated at 10 degrees C and 20°C, 19.05% (4 in 21) of which encode proteins which are related to the immune response (cytokines, chemokines, their receptors, cytokine/chemokines-related genes). Under cold stimulation, the production of the neutrophil chemokine interleukin (IL)-8 and CXC chemokine ligand (CXCL)1 was found remarkably up-regulated by both DNA microarray and qPCR analyses. IL-8 and CXCL1 mRNA were present at detectable levels even in the nontreated control dHMVECs and significantly up-regulated (Ratio 10 centigrade C/37 degrees C: IL8, 1.46±0.13-fold, p=0.0122; CXCL1, 2.40±0.35-fold, p=0.0100) within 2h after cold stimulation and remained elevated for up to 12-h. Up-regulated protein expressions of IL8 and CXCL1 were found in culture medium of dHMVECs and mouse serum after cold stimulation, and also in sera from patients, who suffer from LRWU and cold urticaria. Neutrophil migration in the presence of conditional medium from cold-stimulated dHMVECs is currently under investigation.
Our results showed that cold induced expression of different genes. This is the first time to show that cold can affect the expression profile of chemokines in dHMVECs, which may contribute to the accumulation of neutrophils and inflammation in dermal vascular. They might be candidate biomarkers of diseases resulting from exposure to cold.
Anti-viral immune responses involve the robust production of type-I interferon (IFN-α/β) in plasmacytoid dendritic cells (pDCs). This occurs through the virus-activated MyD88-independent pathway, or ...the TLR7, 9/MyD88 pathways, and is completely dependent on the transcription factor IRF7 1. How type-I IFN is negatively regulated with respect to IRF7 remains unknown.Here we report that peroxisome proliferator-activated receptor gamma (PPAR-γ) is a negative-feedback regulator of IRF7-dependent TLR signaling for type-I IFN production.
WT and PPAR-γ (+/−) mice were used for in vitro stimulation of pDCs with TLR agonists, or i.v delivery of TLR agonists. Levels of type-I IFN in culture supernatants were assessed by ELISA. Interactions between IRF7 and PPAR-γ were studied by FLAG-IRF7 immunoprecipitation and Western blot analysis for PPAR-γ. Pristane (0.5 ml) was injected into WT and PPAR-γ (+/−) C57BL/6 to develop lupus-like disease, or control PBS. Interferon responses in mice were assessed by RT-PCR and ELISAs for autoantibodies.
Through TLR7, 9/MyD88 signaling in pDCs, type-I IFN induces the expression of PPAR-γ, which binds to the DNA-binding domain of IRF7, inhibiting IRF7 activation of type-I IFN genes. A critical role in vivo was confirmed in PPAR-γ (+/−) mice, which displayed enhanced TLR9-type-I IFN induction, compared to WT mice. Using the pristane-induced lupus model (TLR7/MyD88-type-IFN-dependent 2), disease in PPAR-γ (+/−) mice correlated with enhanced type-I IFN production/signaling, type-I IFN-dependent anti-nuclear antibody production and poor survival, compared to in WT mice. Pioglitazone (a PPAR-γ agonist) treatment inhibits murine lupus through a potent inhibitory effect on type-I IFN signaling.
Thus, the role of PPAR-γ in murine lupus, as a key regulator of type-I IFN production, provides a compelling argument for the therapeutic application of PPAR-γ agonists in human lupus, which is considered to be IFN-α-driven 3–5.
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