Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 9 de 9
Filter
Add more filters










Database
Language
Publication year range
1.
Cell Death Differ ; 28(12): 3199-3213, 2021 12.
Article in English | MEDLINE | ID: mdl-34663907

ABSTRACT

SARS-CoV-2 vaccinations have greatly reduced COVID-19 cases, but we must continue to develop our understanding of the nature of the disease and its effects on human immunity. Previously, we suggested that a dysregulated STAT3 pathway following SARS-Co-2 infection ultimately leads to PAI-1 activation and cascades of pathologies. The major COVID-19-associated metabolic risks (old age, hypertension, cardiovascular diseases, diabetes, and obesity) share high PAI-1 levels and could predispose certain groups to severe COVID-19 complications. In this review article, we describe the common metabolic profile that is shared between all of these high-risk groups and COVID-19. This profile not only involves high levels of PAI-1 and STAT3 as previously described, but also includes low levels of glutamine and NAD+, coupled with overproduction of hyaluronan (HA). SARS-CoV-2 infection exacerbates this metabolic imbalance and predisposes these patients to the severe pathophysiologies of COVID-19, including the involvement of NETs (neutrophil extracellular traps) and HA overproduction in the lung. While hyperinflammation due to proinflammatory cytokine overproduction has been frequently documented, it is recently recognized that the immune response is markedly suppressed in some cases by the expansion and activity of MDSCs (myeloid-derived suppressor cells) and FoxP3+ Tregs (regulatory T cells). The metabolomics profiles of severe COVID-19 patients and patients with advanced cancer are similar, and in high-risk patients, SARS-CoV-2 infection leads to aberrant STAT3 activation, which promotes a cancer-like metabolism. We propose that glutamine deficiency and overproduced HA is the central metabolic characteristic of COVID-19 and its high-risk groups. We suggest the usage of glutamine supplementation and the repurposing of cancer drugs to prevent the development of severe COVID-19 pneumonia.


Subject(s)
COVID-19/physiopathology , Glutamine/deficiency , Animals , COVID-19/blood , COVID-19/epidemiology , Comorbidity , Glutamine/blood , Humans , Hyaluronic Acid/blood , Metabolome , Plasminogen Activator Inhibitor 1/blood , Risk Factors , Severity of Illness Index
2.
Cell Death Differ ; 27(12): 3209-3225, 2020 12.
Article in English | MEDLINE | ID: mdl-33037393

ABSTRACT

COVID-19 is caused by SARS-CoV-2 infection and characterized by diverse clinical symptoms. Type I interferon (IFN-I) production is impaired and severe cases lead to ARDS and widespread coagulopathy. We propose that COVID-19 pathophysiology is initiated by SARS-CoV-2 gene products, the NSP1 and ORF6 proteins, leading to a catastrophic cascade of failures. These viral components induce signal transducer and activator of transcription 1 (STAT1) dysfunction and compensatory hyperactivation of STAT3. In SARS-CoV-2-infected cells, a positive feedback loop established between STAT3 and plasminogen activator inhibitor-1 (PAI-1) may lead to an escalating cycle of activation in common with the interdependent signaling networks affected in COVID-19. Specifically, PAI-1 upregulation leads to coagulopathy characterized by intravascular thrombi. Overproduced PAI-1 binds to TLR4 on macrophages, inducing the secretion of proinflammatory cytokines and chemokines. The recruitment and subsequent activation of innate immune cells within an infected lung drives the destruction of lung architecture, which leads to the infection of regional endothelial cells and produces a hypoxic environment that further stimulates PAI-1 production. Acute lung injury also activates EGFR and leads to the phosphorylation of STAT3. COVID-19 patients' autopsies frequently exhibit diffuse alveolar damage (DAD) and increased hyaluronan (HA) production which also leads to higher levels of PAI-1. COVID-19 risk factors are consistent with this scenario, as PAI-1 levels are increased in hypertension, obesity, diabetes, cardiovascular diseases, and old age. We discuss the possibility of using various approved drugs, or drugs currently in clinical development, to treat COVID-19. This perspective suggests to enhance STAT1 activity and/or inhibit STAT3 functions for COVID-19 treatment. This might derail the escalating STAT3/PAI-1 cycle central to COVID-19.


Subject(s)
COVID-19/pathology , STAT Transcription Factors/metabolism , Signal Transduction/physiology , COVID-19/metabolism , COVID-19/virology , Chemokines/metabolism , Cytokines/metabolism , ErbB Receptors/metabolism , Humans , Interferon Type I/metabolism , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , STAT Transcription Factors/chemistry , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism
3.
Inflammation ; 27(4): 191-200, 2003 Aug.
Article in English | MEDLINE | ID: mdl-14527172

ABSTRACT

Stimulation of T cells through the T cell receptor is insufficient for optimal T cell activation. A second activation signal is necessary, being usually provided by the costimulatory molecule CD28. Recently, additional costimulatory pathways have been identified, including inducible costimulator (ICOS) and its ligand B7RP-1. We have examined the role of the B7RP-1/ICOS costimulatory pathway on antigen presentation by B cells, using the I-Ak and I-Ek-positive CH27 B cell line and several different T cell lines. We found that CH27 expressed B7RP-1 and PD-L1 whereas the T cell lines expressed ICOS and PD-1. In the presence of HEL, the T cell hybridomas C10 and 3A9 released IL-2, which is indicative of antigen-specific T cell activation by the CH27 cells. Unexpectedly, blocking antibodies for B7RP-1 and ICOS enhanced the IL-2 response in both T cells. As expected, an increase in the production of IL-2 was seen when blocking antibodies for PD-1 were used. Blocking with antibodies for I-Ak, CD28, B7.1, and B7.2 lead to a decrease in IL-2 production. Additionally we tested a Th1 and a Th2 T cell clone. Blockade of B7RP-1/ICOS lead to an increased IFN-gamma response in Th1 cells (A.E7) and an increased IL-4 response in Th2 cells (D10.G4.1). Intracellular staining also showed an increase in cytokine production when the B7RP-1/ICOS pathway was blocked. In conclusion, the B7RP-1/ICOS pathway is negatively regulating T cell activation by B cells and may play a role similar to that of the PD-L1/PD-1 pathway.


Subject(s)
Antigen Presentation , Antigens, Differentiation, T-Lymphocyte/metabolism , B-Lymphocytes/metabolism , B7-1 Antigen/metabolism , Down-Regulation/immunology , Animals , Antigen Presentation/immunology , Antigens, Differentiation, T-Lymphocyte/physiology , B-Lymphocytes/immunology , B7-1 Antigen/physiology , Cell Line , Cell Line, Tumor , Inducible T-Cell Co-Stimulator Ligand , Inducible T-Cell Co-Stimulator Protein , Mice
4.
Nat Immunol ; 4(9): 899-906, 2003 Sep.
Article in English | MEDLINE | ID: mdl-12925852

ABSTRACT

We investigated the in vivo function of the B7 family member B7-H3 (also known as B7RP-2) by gene targeting. B7-H3 inhibited T cell proliferation mediated by antibody to T cell receptor or allogeneic antigen-presenting cells. B7-H3-deficient mice developed more severe airway inflammation than did wild-type mice in conditions in which T helper cells differentiated toward type 1 (T(H)1) rather than type 2 (T(H)2). B7-H3 expression was consistently enhanced by interferon-gamma but suppressed by interleukin 4 in dendritic cells. B7-H3-deficient mice developed experimental autoimmune encephalomyelitis several days earlier than their wild-type littermates, and accumulated higher concentrations of autoantibodies to DNA. Thus, B7-H3 is a negative regulator that preferentially affects T(H)1 responses.


Subject(s)
B7-1 Antigen/immunology , Th1 Cells/immunology , Animals , Autoantibodies/immunology , Autoantibodies/metabolism , B7 Antigens , B7-1 Antigen/biosynthesis , Dendritic Cells/immunology , Dendritic Cells/metabolism , Down-Regulation/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/pathology , Flow Cytometry , Interferon-gamma/immunology , Interleukin-4/immunology , Lymphocyte Activation/immunology , Lymphocytic choriomeningitis virus/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Orthomyxoviridae/immunology , Receptors, Antigen, T-Cell/immunology , Vesicular stomatitis Indiana virus/immunology
5.
Int J Cancer ; 103(4): 501-7, 2003 Feb 10.
Article in English | MEDLINE | ID: mdl-12478666

ABSTRACT

We have characterized a receptor:ligand pair, ICOS:B7RP-1, that is structurally and functionally related to CD28:B7.1/2. We reported previously that B7RP-1 costimulates T cell proliferation and immune responses (Yoshinaga et al., Nature 1999;402:827-32; Guo et al., J Immunol 2001;166:5578-84; Yoshinaga et al., Int Immunol 2000;12:1439-47). We report that B7RP-1-Fc causes rejection or growth inhibition of Meth A, SA-1 and EMT6 tumors in syngeneic mice. Established Meth A tumors were rejected effectively with a single dose of B7RP-1-Fc, however, the treatment was less effective on larger tumors. Mice that rejected Meth A tumors previously by Day 30, also rejected a subsequent Meth A challenge on Day 60, without additional B7RP-1-Fc treatment, indicating a long-lived memory response. Tumor cells believed to be less immunogenic, such as P815 and EL-4 cells, were less responsive to this treatment. The EL-4 responsiveness to the B7RP-1-Fc treatment was enhanced, however, by pre-treatment of the mice with cyclophosphamide. As expected, T cells appeared to be targeted by B7RP-1-Fc treatment. Thus, the administration of soluble B7RP-1-Fc may have therapeutic value in generating or enhancing anti-tumor activity in a clinical setting.


Subject(s)
B7-1 Antigen/therapeutic use , Neoplasms/therapy , Animals , Antigens, CD/pharmacology , Antineoplastic Agents/therapeutic use , Antineoplastic Agents, Alkylating/pharmacology , B7-2 Antigen , CD3 Complex/biosynthesis , Cell Division/drug effects , Cyclophosphamide/therapeutic use , Cytokines/biosynthesis , Dose-Response Relationship, Drug , Female , Immunohistochemistry , Inducible T-Cell Co-Stimulator Ligand , Ligands , Membrane Glycoproteins/pharmacology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred DBA , Mice, Nude , Neoplasm Transplantation , Time Factors , Tumor Cells, Cultured
6.
J Immunol ; 169(10): 5813-7, 2002 Nov 15.
Article in English | MEDLINE | ID: mdl-12421962

ABSTRACT

The inducible costimulator protein (ICOS) was recently identified as a costimulatory molecule for T cells. Here we analyze the role of ICOS for the acquired immune response of mice against the intracellular bacterium Listeria monocytogenes. During oral L. monocytogenes infection, low levels of ICOS expression were detected by extracellular and intracellular Ab staining of Listeria-specific CD4(+) and CD8(+) T cells. Blocking of ICOS signaling with a soluble ICOS-Ig fusion protein markedly impaired the Listeria-specific T cell responses. Compared with control mice, the ICOS-Ig treated mice generated significantly reduced numbers of Listeria-specific CD8(+) T cells in spleen and liver, as determined by tetramer and intracellular cytokine staining. In contrast, the specific CD8(+) T cell response in the intestinal mucosa did not appear to be impaired by the ICOS-Ig treatment. Analysis of the CD4(+) T cell response revealed that ICOS-Ig treatment also affected the specific CD4(+) T cell response. When restimulated with listerial Ag in vitro, reduced numbers of CD4(+) T cells from infected and ICOS-Ig-treated mice responded with IFN-gamma production. The impaired acquired immune response in ICOS-Ig treated mice was accompanied by their increased susceptibility to L. monocytogenes infection. ICOS-Ig treatment drastically enhanced bacterial titers, and a large fraction of mice succumbed to the otherwise sublethal dose of infection. Thus, ICOS costimulation is crucial for protective immunity against the intracellular bacterium L. monocytogenes.


Subject(s)
Antigens, Differentiation, T-Lymphocyte/physiology , Listeria monocytogenes/immunology , Listeriosis/prevention & control , Lymphocyte Activation/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/microbiology , Administration, Oral , Animals , Antibodies, Blocking/administration & dosage , Antibodies, Blocking/biosynthesis , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/biosynthesis , Antigens, Differentiation, T-Lymphocyte/biosynthesis , Antigens, Differentiation, T-Lymphocyte/immunology , CD4-CD8 Ratio , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/microbiology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/microbiology , Disease Susceptibility/immunology , Epitopes, T-Lymphocyte/analysis , Epitopes, T-Lymphocyte/biosynthesis , Humans , Inducible T-Cell Co-Stimulator Protein , Injections, Intravenous , Injections, Subcutaneous , Interferon-gamma/biosynthesis , Listeriosis/immunology , Lymphocyte Depletion , Mice , Mice, Inbred BALB C , Rats , Rats, Inbred Strains , Recombinant Fusion Proteins/administration & dosage , Recombinant Fusion Proteins/biosynthesis , Signal Transduction/immunology , T-Lymphocyte Subsets/metabolism
7.
J Immunol ; 169(7): 3676-85, 2002 Oct 01.
Article in English | MEDLINE | ID: mdl-12244160

ABSTRACT

The functions of NK cells are regulated by the balance of activating and inhibitory signals. The inhibitory NK cell receptors are well understood; however, less is known about the activating signaling pathways. To explore whether a costimulatory receptor, inducible costimulator (ICOS), is involved in NK cell function, we assessed the role of ICOS in NK cell-mediated cytotoxicity and cytokine production. In addition, to determine whether ICOS contributes to the elimination of tumors in vivo, we examined the tumor growth survival of mice injected with a tumor expressing the ICOS ligand, B7RP-1. We found that ICOS was up-regulated by cytokine stimulation in murine NK cells. Consistent with ICOS expression on activated NK cells, ICOS-dependent cytotoxicity and IFN-gamma production were observed, and appeared to require signaling through the phosphoinositide 3-kinase pathway. Interestingly, ICOS-mediated stimulation allowed activated NK cells to kill more efficiently tumor cells expressing MHC class I. Furthermore, fewer metastases appeared in the liver and spleen of mice injected with the ICOS ligand-expressing tumor compared with mice bearing the parental tumor. These results indicate that NK cell functions are regulated by ICOS.


Subject(s)
Antigens, Differentiation, T-Lymphocyte/physiology , Cytotoxicity, Immunologic/immunology , Interferon-gamma/biosynthesis , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Lymphocyte Activation/immunology , Adjuvants, Immunologic/biosynthesis , Adjuvants, Immunologic/physiology , Animals , Antibodies, Monoclonal/metabolism , Antigens, Differentiation, T-Lymphocyte/biosynthesis , Antigens, Differentiation, T-Lymphocyte/immunology , Antigens, Differentiation, T-Lymphocyte/metabolism , B7-1 Antigen/biosynthesis , B7-1 Antigen/genetics , Cells, Cultured , Cross-Linking Reagents/metabolism , Cytokines/pharmacology , Enzyme Activation/immunology , Growth Inhibitors/physiology , Inducible T-Cell Co-Stimulator Ligand , Inducible T-Cell Co-Stimulator Protein , Killer Cells, Natural/enzymology , Leukemia, Experimental/immunology , Leukemia, Experimental/pathology , Leukemia, Experimental/prevention & control , Ligands , Mice , Mice, Inbred C57BL , Neoplasm Transplantation , Phosphatidylinositol 3-Kinases/metabolism , Protein Biosynthesis , Proteins/physiology , Receptors, Immunologic/physiology , Receptors, Natural Killer Cell , Tumor Cells, Cultured
8.
J Immunol ; 169(3): 1151-8, 2002 Aug 01.
Article in English | MEDLINE | ID: mdl-12133934

ABSTRACT

NF-kappa B-inducing kinase (NIK) is involved in lymphoid organogenesis in mice through lymphotoxin-beta receptor signaling. To clarify the roles of NIK in T cell activation through TCR/CD3 and costimulation pathways, we have studied the function of T cells from aly mice, a strain with mutant NIK. NIK mutant T cells showed impaired proliferation and IL-2 production in response to anti-CD3 stimulation, and these effects were caused by impaired NF-kappa B activity in both mature and immature T cells; the impaired NF-kappa B activity in mature T cells was also associated with the failure of maintenance of activated NF-kappa B. In contrast, responses to costimulatory signals were largely retained in aly mice, suggesting that NIK is not uniquely coupled to the costimulatory pathways. When NIK mutant T cells were stimulated in the presence of a protein kinase C (PKC) inhibitor, proliferative responses were abrogated more severely than in control mice, suggesting that both NIK and PKC control T cell activation in a cooperative manner. We also demonstrated that NIK and PKC are involved in distinct NF-kappa B activation pathways downstream of TCR/CD3. These results suggest critical roles for NIK in setting the threshold for T cell activation, and partly account for the immunodeficiency in aly mice.


Subject(s)
Lymphocyte Activation , Protein Serine-Threonine Kinases/physiology , Receptor-CD3 Complex, Antigen, T-Cell/physiology , T-Lymphocytes/immunology , Animals , B-Cell Lymphoma 3 Protein , I-kappa B Kinase , Interleukin-2/physiology , Mice , NF-kappa B/metabolism , Protein Kinase C/physiology , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/physiology , Tetradecanoylphorbol Acetate/pharmacology , Transcription Factors , NF-kappaB-Inducing Kinase
9.
J Am Soc Nephrol ; 13(6): 1517-26, 2002 Jun.
Article in English | MEDLINE | ID: mdl-12039981

ABSTRACT

MHC class II-expressing renal tubular epithelial cells (TEC) are able to present foreign peptide antigens to T cells. The costimulatory signals that are required for effective T cell activation upon antigen presentation by TEC have not been characterized. Various cultured TEC lines were examined for expression of the recently described costimulatory molecule B7RP-1 (B7h), a ligand of the T cell molecule inducible costimulator (ICOS), and expression was compared with that of B7.1, B7.2, and CD40. B7RP-1 and CD40 were abundantly expressed by cultured murine and human TEC, whereas B7.1 and B7.2 could not be detected. Stimulation with lipopolysaccharide or tumor necrosis factor-alpha did not induce B7.1 or B7.2 expression and did not alter B7RP-1 expression. Interestingly, interleukin-2 production by T cell hybridomas after antigen presentation by TEC was enhanced by blocking antibodies to B7RP-1 and ICOS. In contrast, blocking antibodies to B7RP-1 or ICOS exerted inhibitory effects on anti-CD3-activated murine splenocyte proliferation. Immunohistochemical staining of normal human kidneys demonstrated strong constitutive B7RP-1 expression in distal tubules, collecting ducts, and urothelium. In human kidneys with allograft rejection or interstitial nephritis, distinct B7RP-1 staining was also detected in proximal tubules, in areas of mononuclear infiltration. In conclusion, the B7RP-1/ICOS pathway negatively regulates T cell activation upon MHC class II-restricted antigen presentation by TEC. Because B7RP-1 is also expressed by tubules in vivo, it can be speculated that the B7RP-1/ICOS pathway could play an inhibitory role in TEC-mediated immune activation in the kidney.


Subject(s)
B7-1 Antigen/analysis , Kidney Tubules/chemistry , Animals , Antigen Presentation , Antigens, CD/analysis , Antigens, CD/genetics , Antigens, Differentiation, T-Lymphocyte/physiology , B7-1 Antigen/genetics , B7-1 Antigen/physiology , B7-2 Antigen , CD40 Antigens/analysis , CD40 Antigens/genetics , Cell Line , Epithelial Cells/chemistry , Humans , Immunohistochemistry , Inducible T-Cell Co-Stimulator Ligand , Inducible T-Cell Co-Stimulator Protein , Membrane Glycoproteins/analysis , Membrane Glycoproteins/genetics , Mice , Mice, Inbred C57BL , RNA, Messenger/analysis
SELECTION OF CITATIONS
SEARCH DETAIL
...