Philip Liu
Cornell University, School of Civil and Environmental Engineering, Department Member
ABSTRACT
ABSTRACT
Research Interests:
Aphidicolin is a specific inhibitor of DNA polymerase alpha and blocks DNA synthesis in vivo. The inhibition of purified alpha-polymerase has been shown to be competitive with dCTP but not with the other three deoxynucleoside... more
Aphidicolin is a specific inhibitor of DNA polymerase alpha and blocks DNA synthesis in vivo. The inhibition of purified alpha-polymerase has been shown to be competitive with dCTP but not with the other three deoxynucleoside triphosphates (dNTPs). In order to study the various roles that the alpha-polymerase might play in DNA replication and/or repair, we have attempted to isolate Chinese hamster V79 cells that are resistant to aphidicolin. Four resistant mutants were isolated from BrdU--black light- and UV-mutagenized cells. None of the mutants isolated contains an alpha-polymerase that is resistant, in crude extract measurements, to aphidicolin. Three mutants isolated, however, were found to be resistant to araC. Two mutants tested were found to be sensitive to cytidine and have elevated levels of dCTP or all 4 dNTPs. These results indicate that they are nucleotide pool mutants instead of alpha-polymerase mutants. One mutant, aphr-4, is characterized by the following: (1) high le...
Research Interests: Genetics, Molecular Biology, Biology, DNA replication, Medicine, and 15 moreBiological Sciences, Cell line, Mutation, Animals, Drug Resistance, Lung, Diterpenes, DNA Polymerase, Nucleotides, Biochemistry and cell biology, Chinese hamster, Dna Synthesis, Cricetinae, Medical and Health Sciences, and cytidine
This chapter will examine the role of vitamin D in the innate immune system as a mediator of human host defense mechanisms against microbial disease, focusing on tuberculosis. The first section will examine tuberculosis and the innate... more
This chapter will examine the role of vitamin D in the innate immune system as a mediator of human host defense mechanisms against microbial disease, focusing on tuberculosis. The first section will examine tuberculosis and the innate immune response to the intracellular pathogen, Mycobacterium tuberculosis (M. tuberculosis), the causative agent of tuberculosis. This is followed by a discussion of the known associations, genetic and mechanistic, between the vitamin D pathway and tuberculosis susceptibility. Finally, the chapter will conclude with a discussion on the potential for adjuvant treatment of tuberculosis with vitamin D.
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MR imaging of gene transcription is important as it should enable the non-invasive detection of mRNA alterations in disease. A range of MRI methods have been proposed for in vivo molecular imaging of cells based on the use of ultra-small... more
MR imaging of gene transcription is important as it should enable the non-invasive detection of mRNA alterations in disease. A range of MRI methods have been proposed for in vivo molecular imaging of cells based on the use of ultra-small super-paramagnetic iron oxide (USPIO) nanoparticles and related susceptibility weighted imaging methods. Although immunohistochemistry can robustly differentiate the expression of protein variants, there is currently no direct gene assay technique that is capable of differentiating established to differentiate the induction profiles of c-Fos mRNA in vivo. To visualize the differential FosB gene expression profile in vivo after burn trauma, we developed MR probes that link the T2* contrast agent [superparamagnetic iron oxide nanoparticles (SPION)] with an oligodeoxynucleotide (ODN) sequence complementary to FosB mRNA to visualize endogenous mRNA targets via in vivo hybridization. The presence of this SPION-ODN probe in cells results in localized sign...
Research Interests: Chemistry, Molecular Biology, Burn, Medicine, Gene expression, and 3 moreMolecular Imaging, c-Fos, and In Vivo
A major consequence of microbial infection is the tissue injury that results from the host inflammatory response. In acne, inflammation is due in part to the ability of Propionibacterium acnes to activate TLR2. Because all-trans retinoic... more
A major consequence of microbial infection is the tissue injury that results from the host inflammatory response. In acne, inflammation is due in part to the ability of Propionibacterium acnes to activate TLR2. Because all-trans retinoic acid (ATRA) decreases inflammation in acne, we investigated whether it regulates TLR2 expression and function. Treatment of primary human monocytes with ATRA led to the down-regulation of TLR2 as well as its coreceptor CD14, but not TLR1 or TLR4. The ability of a TLR2/1 ligand to trigger monocyte cytokine release was inhibited by pre- and cotreatment with ATRA; however, TLR4 activation was affected by cotreatment only. ATRA also down-regulated monocyte cytokine induction by P. acnes. These data indicate that ATRA exerts an anti-inflammatory effect on monocytes via two pathways, one specifically affecting TLR2/1 and CD14 expression and one independent of TLR expression. Agents that target TLR expression and function represent a novel strategy to trea...
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Propionibacterium acnes is a major etiological factor of acne, triggering an inflammatory response in part through the activation of TLR2. In this study, we demonstrate that activation of peripheral blood monocytes with P. acnes in vitro... more
Propionibacterium acnes is a major etiological factor of acne, triggering an inflammatory response in part through the activation of TLR2. In this study, we demonstrate that activation of peripheral blood monocytes with P. acnes in vitro induced their differentiation into two distinct innate immune cell subsets, CD209(+) macrophages and CD1b(+) dendritic cells. Furthermore, P. acnes induced expression of mRNA for the cytokines IL-15 and GM-CSF, which differentiate CD209(+) and CD1b(+) cells, respectively. The CD209(+) cells were more effective in uptake of P. acnes, compared with the CD1b(+) cells, and demonstrated a 2-fold greater antimicrobial activity against the phagocytosed bacteria. Although CD1b(+) cells secreted inflammatory cytokines in response to both P. acnes and a TLR2 ligand control, the CD209(+) cells responded only to P. acnes. The addition of all-trans retinoic acid, a commonly used agent for the treatment of acne, directly induced differentiation of monocytes into ...
Research Interests:
Research Interests:
Research Interests: Endocrinology, Biology, Calcium, Medicine, Internal Medicine, and 3 moreBone, Vitamin, and Endocrine System
Immunomodulatory responses to the active form of vitamin D (1,25-dihydroxyvitamin D, 1,25D) have been recognized for many years, but it is only in the last 5 years that the potential role of this in normal human immune function has been... more
Immunomodulatory responses to the active form of vitamin D (1,25-dihydroxyvitamin D, 1,25D) have been recognized for many years, but it is only in the last 5 years that the potential role of this in normal human immune function has been recognized. Genome-wide analyses have played a pivotal role in redefining our perspective on vitamin D and immunity. The description of increased vitamin D receptor (VDR) and 1α-hydroxylase (CYP27B1) expression in macrophages following a pathogen challenge, has underlined the importance of intracrine vitamin D as key mediator of innate immune function. It is now clear that both macrophages and dendritic cells (DCs) are able to respond to 25-hydroxyvitamin D (25D), the major circulating vitamin D metabolite, thereby providing a link between the function of these cells and the variations in vitamin D status common to many humans. The identification of hundreds of primary 1,25D target genes in immune cells has also provided new insight into the role of ...
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Tuberculosis is a leading cause of infectious disease-related death worldwide; however, only 10% of people infected with Mycobacterium tuberculosis develop disease. Factors that contribute to protection could prove to be promising targets... more
Tuberculosis is a leading cause of infectious disease-related death worldwide; however, only 10% of people infected with Mycobacterium tuberculosis develop disease. Factors that contribute to protection could prove to be promising targets for M. tuberculosis therapies. Analysis of peripheral blood gene expression profiles of active tuberculosis patients has identified correlates of risk for disease or pathogenesis. We sought to identify potential human candidate markers of host defense by studying gene expression profiles of macrophages, cells that, upon infection by M. tuberculosis, can mount an antimicrobial response. Weighted gene coexpression network analysis revealed an association between the cytokine interleukin-32 (IL-32) and the vitamin D antimicrobial pathway in a network of interferon-γ- and IL-15-induced "defense response" genes. IL-32 induced the vitamin D-dependent antimicrobial peptides cathelicidin and DEFB4 and to generate antimicrobial activity in vitro, ...
Research Interests: Immunology, Biomarkers, Biology, Vitamin D, Macrophages, and 13 moreMedicine, Biological Sciences, Cell Differentiation, Tuberculosis, Humans, Mycobacterium tuberculosis, Antimicrobial Cationic Peptides, Interleukins, Biological markers, Gene expression profiling, Interleukin, Interferon gamma, and Medical and Health Sciences
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Research Interests:
Research Interests:
To circumvent the limitations of using postmortem brain in molecular assays, we used avidin–biotin binding to couple superparamagnetic iron oxide nanoparticles (SPIONs) (15–20 nm) to phosphorothioate-modified oligodeoxynucleotides (sODNs)... more
To circumvent the limitations of using postmortem brain in molecular assays, we used avidin–biotin binding to couple superparamagnetic iron oxide nanoparticles (SPIONs) (15–20 nm) to phosphorothioate-modified oligodeoxynucleotides (sODNs) with sequence complementary to c-fosand β-actinmRNA (SPION-cfos and SPION-βactin, respectively) (14–22 nm). The Stern–Volmer constant for the complex of SPION and fluorescein isothiocyanate (FITC)-sODN is 3.1 × 106/m. We studied the feasibility of using the conjugates forin vivomagnetic resonance imaging (MRI) to monitor gene transcription, and demonstrated that these complexes at 40 μg of Fe per kilogram of body weight were retained at least 1 d after intracerebroventricular infusion into the left ventricle of C57Black6 mice. SPION retention measured by MRI as T2* or R2* maps (R2* = 1/T2*) was compared with histology of iron oxide (Prussian blue) and FITC-labeled sODN. We observed significant reduction in magnetic resonance (MR) T2* signal in the ...
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Research Interests: Magnetic Resonance Imaging, Biology, Magnetic Resonance Spectroscopy, Medicine, Metal Nanoparticles, and 15 moreIn Situ Hybridization, Cardiac arrest, Mice, Animals, Male, Magnetic Resonance, Central Nervous System, Iron Oxide, Brain Ischemia, Medical Physiology, Cerebral Ischemia, Ferric Compounds, Contrast Media, Biochemistry and cell biology, and Carotid Stenosis
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Vitamin D is required for both innate and adaptive immunity to tuberculosis.
Research Interests: Microbiology, Science, Biology, Antimicrobial Peptides, Macrophages, and 15 moreAutophagy, Medicine, Biological Sciences, Cathelicidin, Humans, Mycobacterium tuberculosis, Immunity, Macrophage, Antimicrobial, Immune system, Antimicrobial Cationic Peptides, Monocytes, Innate Immune System, Interferon gamma, and Medical and Health Sciences
In innate immune responses, activation of Toll-like receptors (TLRs) triggers direct antimicrobial activity against intracellular bacteria, which in murine, but not human, monocytes and macrophages is mediated principally by nitric oxide.... more
In innate immune responses, activation of Toll-like receptors (TLRs) triggers direct antimicrobial activity against intracellular bacteria, which in murine, but not human, monocytes and macrophages is mediated principally by nitric oxide. We report here that TLR activation of human macrophages up-regulated expression of the vitamin D receptor and the vitamin D-1–hydroxylase genes, leading to induction of the antimicrobial peptide cathelicidin and killing of intracellular Mycobacterium tuberculosis . We also observed that sera from African-American individuals, known to have increased susceptibility to tuberculosis, had low 25-hydroxyvitamin D and were inefficient in supporting cathelicidin messenger RNA induction. These data support a link between TLRs and vitamin D–mediated innate immunity and suggest that differences in ability of human populations to produce vitamin D may contribute to susceptibility to microbial infection.
Research Interests: Microbiology, Biology, Antimicrobial Peptides, Macrophages, Innate immunity, and 15 moreMedicine, Disease susceptibility, Dendritic Cells, Cathelicidin, Humans, African American, Antimicrobial activity, Calcitriol, Antimicrobial Peptide, African Americans, Immune system, Antimicrobial Cationic Peptides, Monocytes, Innate Immune System, and innate immune response
We have tested a hypothesis that the natural product curcuminoids, which has epidemiologic and experimental rationale for use in AD, may improve the innate immune system and increase amyloid-β (Aβ) clearance from the brain of patients... more
We have tested a hypothesis that the natural product curcuminoids, which has epidemiologic and experimental rationale for use in AD, may improve the innate immune system and increase amyloid-β (Aβ) clearance from the brain of patients with sporadic Alzheimer's disease (AD). Macrophages of a majority of AD patients do not transport Aβ into endosomes and lysosomes, and AD monocytes do not efficiently clear Aβ from the sections of AD brain, although they phagocytize bacteria. In contrast, macrophages of normal subjects transport Aβ to endosomes and lysosomes, and monocytes of these subjects clear Aβ in AD brain sections. Upon Aβ stimulation, mononuclear cells of normal subjects up-regulate the transcription of β-1,4-mannosyl-glycoprotein 4-β- N -acetylglucosaminyltransferase ( MGAT3 ) ( P < 0.001) and other genes, including Toll like receptors ( TLRs ), whereas mononuclear cells of AD patients generally down-regulate these genes. Defective phagocytosis of Aβ may be related to do...
Research Interests: Biology, Macrophages, Innate immunity, Medicine, Multidisciplinary, and 15 moreToll like receptor signaling, Toll Like Receptors, Humans, Curcumin, Immunotherapy, Endosome, Aged, Phagocytosis, Cell communication, Lymphocytes, Alzheimer Disease, Protein Transport, Protein Biosynthesis, Innate Immune System, and TLR
We investigated the mechanisms by which T-cell cytokines are able to influence the Toll-like receptor (TLR)-induced, vitamin D-dependent antimicrobial pathway in human monocytes. T-cell cytokines differentially influenced TLR2/1-induced... more
We investigated the mechanisms by which T-cell cytokines are able to influence the Toll-like receptor (TLR)-induced, vitamin D-dependent antimicrobial pathway in human monocytes. T-cell cytokines differentially influenced TLR2/1-induced expression of the antimicrobial peptides cathelicidin and DEFB4, being up-regulated by IFN-γ, down-regulated by IL-4, and unaffected by IL-17. The Th1 cytokine IFN-γ up-regulated TLR2/1 induction of 25-hydroxyvitamin D-1α-hydroxylase (i.e., CYP27B1), leading to enhanced bioconversion of 25-hydroxyvitamin D3(25D3) to its active metabolite 1,25D3. In contrast, the Th2 cytokine IL-4, by itself and in combination with the TLR2/1 ligand, induced catabolism of 25D3to the inactive metabolite 24,25D3, and was dependent on expression of vitamin D-24-hydroxylase (i.e., CYP24A1). Therefore, the ability of T-cell cytokines to differentially control monocyte vitamin D metabolism represents a mechanism by which cell-mediated immune responses can regulate innate im...
Research Interests: Biology, Cytokines, Medicine, Gene expression, Multidisciplinary, and 15 moreSignal Transduction, Cathelicidin, Humans, Calcitriol, T lymphocytes, Cytokine, Immune system, Antimicrobial Cationic Peptides, Monocytes, Beta Defensins, Interleukin, Interferon gamma, TLR, reverse transcriptase polymerase chain reaction, and Monocyte
Research Interests: Biology, Antimicrobial Peptides, Cell Biology, Medicine, Multidisciplinary, and 15 moreCathelicidin, Humans, Models, Antimicrobial activity, Biological, Calcitriol, Antimicrobial Cationic Peptides, Monocytes, Human Activity, Beta Defensins, Gene Expression Regulation, Innate Immune System, Host Defense, Genetic, and innate immune response
Research Interests: Immunology, Immune response, Biology, Medicine, Cathelicidin, and 15 moreHumans, Leprosy, Antimicrobial activity, Immune regulation, Antimicrobial, Antimicrobial Peptide, Immune system, Cells, Antimicrobial Cationic Peptides, Beta Defensins, Clinical Presentation, Interleukin, Differential expression, Cultured, and Medical and Health Sciences
ABSTRACT
Research Interests: Immunology, Biology, Cytokines, Public Health, Medicine, and 15 moreSignal Transduction, DNA, Humans, Lymphatic Filariasis, Schistosomiasis, Animals, CpG islands, Dendritic cell, Nucleic Acid, Innate Immune System, TLR, innate immune response, Immunologic, Medical and Health Sciences, and Pharmacology and pharmaceutical sciences
Research Interests: Immunology, Biology, Cell Biology, Macrophages, Medicine, and 15 moreGene expression, Nature, Dendritic Cells, Cell Differentiation, Humans, Leprosy, Infectious Disease, Macrophage, Dendritic cell, Monocytes, Disease Progression, Cell Adhesion Molecules, Innate Immune System, Host Defense, and Medical and Health Sciences
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Research Interests:
Recent studies using ischemia/reperfusion models of brain injury suggest that there is a period of time during which the formation of oxidative DNA lesions (ODLs) exceeds removal. This interval is a window of opportunity in which to study... more
Recent studies using ischemia/reperfusion models of brain injury suggest that there is a period of time during which the formation of oxidative DNA lesions (ODLs) exceeds removal. This interval is a window of opportunity in which to study the effect of gene damage on gene expression in the brain, because the presence of excessive ODLs mimics a deficiency in gene repair, which has been shown to be associated with neurological disorders. Evidence from studies using similar models indicates that expression of faulty transcripts from ODL‐infested genes and non‐sense mutation in repaired genes occur before the process of cell death. Preventing the formation of ODLs and enhancing ODL repair are shown to increase the expression of intact transcripts and attenuate cell death. Understanding this mechanism could lead to the development of therapeutic techniques (physiologic, pharmacological, and/or genomic) that can enhance recovery. © 2002 Wiley‐Liss, Inc.
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Research Interests: Immunology, Flow Cytometry, Biomarkers, Macrophages, Innate immunity, and 15 moreMedicine, Amyotrophic Lateral Sclerosis, Brain, Humans, Female, Male, Amyloid Beta, Aged, Biomarker, Biological markers, Encephalitis, Alzheimer Disease, Early Diagnosis, Gene Expression Regulation, and Innate Immune System
Research Interests: Biology, Neurochemistry, DNA repair, Medicine, DNA, and 9 moreStroke, Brain, Animals, Male, Two Stroke Engine, Cell nucleus, Rats, Neurosciences, and Brain injuries
The repair enzyme 8‐oxoguanine glycosylase/apyrimidinic/apurinic lyase (OGG) removes 8‐hydroxy‐2′‐deoxyguanosine (oh8dG) in human cells. Our goal was to examine oh8dG‐removing activity in the cell nuclei of male C57BL/6 mouse brains... more
The repair enzyme 8‐oxoguanine glycosylase/apyrimidinic/apurinic lyase (OGG) removes 8‐hydroxy‐2′‐deoxyguanosine (oh8dG) in human cells. Our goal was to examine oh8dG‐removing activity in the cell nuclei of male C57BL/6 mouse brains treated with either forebrain ischemia‐reperfusion (FbIR) or sham operations. We found that the OGG activity in nuclear extracts, under the condition in which other nucleases did not destroy the oligodeoxynucleotide duplex, excised oh8dG with the greatest efficiency on the oligodeoxynucleotide duplex containing oh8dG/dC and with less efficiency on the heteroduplex containing oh8dG/dT, oh8dG/dG, or oh8dG/dA. This specificity was the same as for the recombinant type 1 OGG (OGG1) of humans. We observed that the OGG1 peptide and its activity in the mouse brain were significantly increased after 90 min of ischemia and 20‐30 min of reperfusion. The increase in the protein level and in the activity of brain OGG1 correlated positively with the elevation of FbIR‐...
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The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D) enhances innate immunity by inducing the cathelicidin antimicrobial peptide (hCAP). In monocytes/macrophages, this occurs primarily in response to activation of TLR, that... more
The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D) enhances innate immunity by inducing the cathelicidin antimicrobial peptide (hCAP). In monocytes/macrophages, this occurs primarily in response to activation of TLR, that induce expression of the vitamin D receptor and localized synthesis of 1,25(OH)2D from precursor 25-hydroxyvitamin D3 (25OHD). To clarify the relationship between vitamin D and innate immunity, we assessed changes in hCAP expression in vivo and ex vivo in human subjects attending a bone clinic (n = 50). Of these, 38% were vitamin D-insufficient (<75 nM 25OHD) and received supplementation with vitamin D (50,000 IU vitamin D2 twice weekly for 5 wk). Baseline 25OHD status or vitamin D supplementation had no effect on circulating levels of hCAP. Therefore, ex vivo changes in hCAP for each subject were assessed using peripheral blood monocytes cultured with 10% autologous serum (n = 28). Under these vitamin D “insufficient” conditions the TLR2/1 ligan...
Research Interests: Endocrinology, Immunology, Biology, Immunology of the Gut, Innate immunity, and 15 moreMedicine, Gene expression, Cathelicidin, Humans, Internal Medicine, Female, Disease resistance, Male, Enzyme, Middle Aged, In Vivo, Antimicrobial Cationic Peptides, Enzyme Linked Immunosorbent Assay, Monocyte, and ex vivo
Langerhans cells (LC) are a unique subset of dendritic cells (DC), present in the epidermis and serving as the first line of defense against pathogens invading the skin. To investigate the role of human LCs in innate immune responses, we... more
Langerhans cells (LC) are a unique subset of dendritic cells (DC), present in the epidermis and serving as the first line of defense against pathogens invading the skin. To investigate the role of human LCs in innate immune responses, we examined TLR expression and function of LC-like DCs derived from CD34+ progenitor cells and compared them to DCs derived from peripheral blood monocytes (monocyte-derived DC; Mo-DC). LC-like DCs and Mo-DCs expressed TLR1–10 mRNAs at comparable levels. Although many of the TLR-induced cytokine patterns were similar between the two cell types, stimulation with the TLR3 agonist poly(I:C) triggered significantly higher amounts of the IFN-inducible chemokines CXCL9 (monokine induced by IFN-γ) and CXCL11 (IFN-γ-inducible T cell α chemoattractant) in LC-like DCs as compared with Mo-DCs. Supernatants from TLR3-activated LC-like DCs reduced intracellular replication of vesicular stomatitis virus in a type I IFN-dependent manner. Finally, CXCL9 colocalized wi...
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An essential function of the innate immune system is to directly trigger antimicrobial mechanisms to defend against invading pathogens. In humans, one such pathway involves activation by TLR2/1L leading to the vitamin D-dependent... more
An essential function of the innate immune system is to directly trigger antimicrobial mechanisms to defend against invading pathogens. In humans, one such pathway involves activation by TLR2/1L leading to the vitamin D-dependent induction of antimicrobial peptides. In this study, we found that TLR2/1-induced IL-15 was required for induction of CYP27b1, the VDR and the downstream antimicrobial peptide cathelicidin. Although both IL-15 and IL-4 triggered macrophage differentiation, only IL-15 was sufficient by itself to induce CYP27b1 and subsequent bioconversion of 25-hydroxyvitamin D3 (25D3) into bioactive 1,25D3, leading to VDR activation and induction of cathelicidin. Finally, IL-15-differentiated macrophages could be triggered by 25D3 to induce an antimicrobial activity against intracellular Mycobacterium tuberculosis. Therefore, IL-15 links TLR2/1-induced macrophage differentiation to the vitamin D-dependent antimicrobial pathway.