Induction of indoleamine 2,3-dioxygenase 1 expression in neurons of the central nervous system through inhibition of histone deacetylases blocks the progression of experimental autoimmune encephalomyelitis.

Background: A wide array of histone deacetylase (HDAC) inhibitors and aryl hydrocarbon receptor (AHR) agonists commonly arrest experimental autoimmune encephalomyelitis (EAE). However, it is not known whether HDAC inhibition is linked to the AHR signaling pathway in EAE.

Methods: We investigated how the pan-HDAC inhibitor SB939 (pracinostat) exerted immunoregulatory action in the myelin oligodendrocyte glycoprotein 35-55 (MOG)-induced EAE mouse model by evaluating changes in of signal transducer and activator of transcription 3 (STAT3) acetylation and the expression of indoleamine 2,3-dioxygenase 1 (IDO1) and AHR in inflamed spinal cords during EAE evolution.

Immune regulation through tryptophan metabolism.

Amino acids are fundamental units of molecular components that are essential for sustaining life; however, their metabolism is closely interconnected to the control systems of cell function. Tryptophan (Trp) is an essential amino acid catabolized by complex metabolic pathways. Several of the resulting Trp metabolites are bioactive and play central roles in physiology and pathophysiology.

Priming Mesenchymal Stem/Stromal Cells with a Combination of a Low Dose of IFN-γ and Bortezomib Results in Potent Suppression of Pathogenic Th17 Immunity Through the IDO1-AHR Axis.

Preconditioning of mesenchymal stem/stromal cells (MSCs) with the inflammatory cytokine IFN-γ enhances not only their immunosuppressive activity but also their expression of HLA and proinflammatory genes. We hypothesized that prevention of the upregulation of inflammatory cytokines and HLA molecules in IFN-γ-primed MSCs would render these cells more immunosuppressive and less immunogenic. In this study, we discovered the following findings supporting this hypothesis: (1) activated human T cells induced the expression of IDO1 in MSCs via IFN-γ secretion and those MSCs in turn inhibited T-cell proliferation in an AHR-dependent fashion; (2) there was no difference in the expression of IDO1 and HLA-DR in MSCs after priming with a low dose (25 IU/mL) versus a high dose (100 IU/mL) of IFN-γ; (3) the transient addition of bortezomib, a proteasome inhibitor, to culture MSCs after IFN-γ priming decreased the expression of HLA-DR, inflammatory cytokine genes and Vcam1 while increasing the expression of IDO1 and the production of L-kynurenine; finally, MSCs primed with a combination of a low dose of IFN-γ and bortezomib were more effective in inhibiting Th17-mediated idiopathic pneumonia syndrome (IPS) and chronic colitis than unprimed MSCs.

GSPE Protects against Bleomycin-Induced Pulmonary Fibrosis in Mice via Ameliorating Epithelial Apoptosis through Inhibition of Oxidative Stress.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown cause which leads to alveolar epithelial cell apoptosis followed by basement membrane disruption and accumulation of extracellular matrix, destroying the lung architecture. Oxidative stress is involved in the development of alveolar injury, inflammation, and fibrosis. Oxidative stress-mediated alveolar epithelial cell (AEC) apoptosis is suggested to be a key process in the pathogenesis of IPF.

Aryl hydrocarbon receptor-targeted therapy for CD4+ T cell-mediated idiopathic pneumonia syndrome in mice.

We previously demonstrated that interferon γ (IFN-γ) derived from donor T cells co-opts the indoleamine 2,3-dioxygenase 1 (IDO1) → aryl hydrocarbon receptor (AHR) axis to suppress idiopathic pneumonia syndrome (IPS). Here we report that the dysregulated expression of AP-1 family genes in Ahr-/- lung epithelial cells exacerbated IPS in allogeneic bone marrow transplantation settings. AHR repressed transcription of Jund by preventing STAT1 from binding to its promoter.

IL-33 Coordinates Innate Defense to Systemic Infection by Regulating IL-23 and IL-10 in an Opposite Way.

Invasive candidiasis has high mortality rates in immunocompromised patients, causing serious health problems. In mouse models, innate immunity protects the host by rapidly mobilizing a variety of resistance and tolerance mechanisms to systemic infection. We have previously demonstrated that exogenous IL-33 regulates multiple steps of innate immunity involving resistance and tolerance processes.

CD137 Signaling Is Critical in Fungal Clearance during Systemic Infection.

Invasive fungal infections by frequently cause mortality in immunocompromised patients. Neutrophils are particularly important for fungal clearance during systemic infection, yet little has been known regarding which surface receptor controls neutrophils' antifungal activities. CD137, which is encoded by , belongs to the tumor necrosis receptor superfamily and has been shown to regulate neutrophils in Gram-positive bacterial infection.

CCR5-mediated Recruitment of NK Cells to the Kidney Is a Critical Step for Host Defense to Systemic Infection.

C-C chemokine receptor type 5 (CCR5) regulates the trafficking of various immune cells to sites of infection. In this study, we showed that expression of CCR5 and its ligands was rapidly increased in the kidney after systemic infection, and infected CCR5 mice exhibited increased mortality and morbidity, indicating that CCR5 contributes to an effective defense mechanism against systemic infection. The susceptibility of CCR5 mice to infection was due to impaired fungal clearance, which in turn resulted in exacerbated renal inflammation and damage.

Repression of PPARγ reduces the ABCG2-mediated efflux activity of M2 macrophages.

Even though subclasses of macrophage have distinct roles during progression of infectious diseases, it remains poorly understood whether there is a subset-specific difference in drug responses. Here, we report that ABCG2 was expressed specifically in M2-like macrophages and that it controlled their efflux activities. Abcg2 expression is markedly induced during polarization of PMA-primed macrophages toward an M2 type.

Identification of CD137- and CD137L-Expressing Cells in EL-4 Tumor.

The tumor microenvironment (TME) contains noncancerous cells such as various types of immune cells and fibroblasts. Cancer cells direct these stromal cells to create a microenvironment favorable for tumor growth and intercellular interactions have a critical role in this process. In established tumors, interactions between CD137 and its ligand (CD137L) contribute to tumor immune evasion and tumor growth.

CD137 Signaling Regulates Acute Colitis via RALDH2-Expressing CD11bCD103 DCs.

CD137, a potent costimulatory receptor for CD8 T cells, is expressed in various non-T cells, but little is known about its regulatory functions in these cells. In this study, we show that CD137 signaling, specifically in intestinal CD11bCD103 dendritic cells (DCs), restricts acute colitis progression. Mechanistically, CD137 engagement activates TAK1 and subsequently stimulates the AMPK-PGC-1α axis to enhance expression of the Aldh1a2 gene encoding the retinoic acid (RA) metabolizing enzyme RALDH2.

Simultaneous determination of eight arginine-related metabolites in cellular extracts using liquid chromatography-tandem mass spectrometry.

A simple, sensitive, and rapid liquid chromatography (LC)-tandem mass spectrometry (MS/MS) method was developed for the simultaneous determination of arginine and its pathway-related metabolites (ornithine, proline, citrulline, glutamate, agmatine, spermidine, and spermine) in cellular extracts. Cells were lysed and cellular proteins precipitated by the addition of acetonitrile followed by ultra-sonication. Supernatants were analyzed using a Chromolith High Resolution RP-18 endcapped column (100 × 4.

Optimized Gemcitabine Therapy in Combination with E7 Peptide Immunization Elicits Tumor Cure by Preventing Ag-Specific CTL Inhibition in Animals with Large Established Tumors.

The role of chemotherapeutic agents in tumor immunotherapy is still controversial. In this study, we test using a TC-1 tumor model whether gemcitabine plus E7 peptide vaccine regimens (E7 peptides+CpG-ODN+anti-4-1BB Abs) may result in tumor cure in mice with large established tumors, with a focus on their effects on Ag-specific cytotoxic T lymphocyte (CTL) and myeloid-derived suppressor cell levels. Gemcitabine inhibited tumor growth by its direct cytotoxicity to tumor cells in vivo.

Anti-CD137 Suppresses Tumor Growth by Blocking Reverse Signaling by CD137 Ligand.

CD137 (4-1BB) is a T-cell costimulatory molecule, and agonstic CD137 antibodies are currently being evaluated in the clinic as cancer immunotherapy. Recently, it was found that CD137 mice or mice injected with agonistic anti-CD137 antibodies exhibit heightened antitumor responses, contrary to expectations based on other knowledge of CD137 function. Here, we report findings related to reverse signaling by CD137 ligand (CD137L) in antigen-presenting dendritic cells (DC) in tumors that address these paradoxical results.

Inhibition of acute lethal pulmonary inflammation by the IDO-AhR pathway.

The lung is a prototypic organ that was evolved to reduce immunopathology during the immune response to potentially hazardous endogenous and exogenous antigens. In this study, we show that donor CD4 T cells transiently induced expression of indoleamine 2,3-dioxygenase (IDO) in lung parenchyma in an IFN-γ-dependent manner early after allogeneic hematopoietic stem cell transplantation (HSCT). Abrogation of host IDO expression by deletion of the IDO gene or the IFN-γ gene in donor T cells or by FK506 treatment resulted in acute lethal pulmonary inflammation known as idiopathic pneumonia syndrome (IPS).

Roles of IL-33 in Resistance and Tolerance to Systemic Candida albicans Infections.

IL-33 is a multifunctional cytokine that is released in response to a variety of intrinsic and extrinsic stimuli. The role of IL-33 in Candida albicans infections is just beginning to be revealed. This cytokine has beneficial effects on host defense against systemic C.

Intratumorally Establishing Type 2 Innate Lymphoid Cells Blocks Tumor Growth.

A long-standing question in the field of tumor immunotherapy is how Th2 cytokines block tumor growth. Their antitumor effects are particularly prominent when they are secreted continuously in tumors, suggesting that Th2 cytokines may create a tumor microenvironment unfavorable for tumor growth independently of adaptive immunity. In this study, we show that local production of IL-33 establishes a high number of type 2 innate lymphoid cells (ILC2s) with potent antitumor activity.

Involvement of Protein Kinase C-δ in Vascular Permeability in Acute Lung Injury.

Pulmonary edema is a major cause of mortality due to acute lung injury (ALI). The involvement of protein kinase C-δ (PKC-δ) in ALI has been a controversial topic. Here we investigated PKC-δ function in ALI using PKC-δ knockout (KO) mice and PKC inhibitors.

Is CD137 Ligand (CD137L) Signaling a Fine Tuner of Immune Responses?

Now, it has been being accepted that reverse signaling through CD137 ligand (CD137L) plays an important role in vivo during hematopoiesis and in immune regulation. However, due to technical difficulty in dissecting both directional signaling events simultaneously in vivo, most biological activities caused by CD137-CD137L interactions are considered as results from signaling events of the CD137 receptor. To make the story more complex, CD137(-/-) and CD137L(-/-) mice have increased or decreased immune responses in a context-dependent manner.