bx795 and Inflammation

Treg cells have been shown to be an important part of immune-homeostasis and IL-2 which is produced upon T cell receptor (TCR)-dependent activation of T lymphocytes has been demonstrated to critically participate in Treg development.. To evaluate small molecule inhibitors (SMI) for the identification of novel IL-2/Treg enhancing compounds.. We used TCR-dependent and allergen-specific cytokine secretion of human and mouse T cells, next generation messenger ribonucleic acid sequencing (RNA-Seq) and two different models of allergic airway inflammation to examine lead SMI-compounds.. We show here that the reported 3-phosphoinositide dependent kinase-1 (PDK1) SMI BX-795 increased IL-2 in culture supernatants of Jurkat E6-1 T cells, human peripheral blood mononuclear cells (hPBMC) and allergen-specific mouse T cells upon TCR-dependent and allergen-specific stimulation while concomitantly inhibiting Th2 cytokine secretion. RNA-Seq revealed that the presence of BX-795 during allergen-specific activation of T cells induces a. BX-795 potently uncouples IL-2 production from Th2 inflammation and induces Th-IL-2 cells, which highly resemble induced (i)Tregs. Thus, BX-795 may be a useful new compound for the treatment of allergic diseases.

Topics: Allergens; Animals; Cytokines; Humans; Inflammation; Interleukin-2; Leukocytes, Mononuclear; Mice; Receptors, Antigen, T-Cell; Th2 Cells

Glioma are common malignant brain tumors, among which glioblastoma multiforme (GBM) has the worst prognosis. Different studies of GBM revealed that targeting nuclear factor B (NF-B) induced an attenuation tumor proliferation and prolonged cell survival. TBK1 {TANK [TRAF (TNF (tumor-necrosis-factor) receptor-associated factor)-associated NF-B activator]-binding kinase 1} is a serine/threonine protein kinase, and it is a member of the IB kinase (IKK) family involved in NF-B pathway activation. The aim of this study was to investigate the potential effect of BX795, an inhibitor of TBK1, in an in vitro and ex vivo model of GBM. GBM cell lines (U87 and U138) and primary GBM cells were treated with different concentrations of BX795 at different time points (24, 48, and 72h) to evaluate cell viability, autophagy, inflammation, and apoptosis. Our results demonstrated that BX795 10 M was able to reduce cell viability, showing antiproliferative effect in U87, U138, and primary GBM cells. Moreover, treatment with BX795 10 M increased the proapoptotic proteins Bax, p53, caspase 3, and caspase 9, whereas the antiapoptotic Bcl-2 expression was reduced. Additionally, our results showed a marked decrease in autophagy following BX795 treatment, reducing Atg 7, Atg 5/12, and AKT expression. The anti-inflammatory effect of BX795 was demonstrated by a significantly reduction in NIK, IKK, and TNF- expression, accompanied by a downregulation of angiogenesis. Furthermore, in primary GBM cell, BX795 10 M was able to reduce TBK1 pathway activation and SOX3 expression. In conclusion, these findings showed that TBK1 is involved in GBM proliferation, demonstrating that the inhibitor BX795, thanks to its abilities, could improve therapeutic strategies for GBM treatment.

Topics: Antineoplastic Agents; Apoptosis; Autophagy; Brain Neoplasms; Caspase 3; Caspase 9; Cell Line, Tumor; Cell Proliferation; Cell Survival; Glioblastoma; Humans; I-kappa B Kinase; Inflammation; NF-kappa B; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Pyrimidines; Signal Transduction; Thiophenes