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  • The American Association of Immunologists (AAI)  (3)
  • The American Society for Pharmacology and Experimental Therapeutics (ASPET)  (3)
  • 1
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    Vesnarinone Suppresses TNF{alpha} mRNA Expression by Inhibiting Valosin-Containing Protein [Articles] (2013)
    The American Society for Pharmacology and Experimental Therapeutics (ASPET)
    Details
    Publication Date: 2013-04-16
    Description: Vesnarinone is a synthetic quinolinone derivative used in the treatment of cardiac failure and cancer. It is also known to cause agranulocytosis as a side effect, which restricts its use, although the mechanism underlying agranulocytosis is not well understood. Here, we show that vesnarinone binds to valosin-containing protein (VCP), which interacts with polyubiquitinated proteins and is essential for the degradation of I B α to activate nuclear factor (NF) B. We show that vesnarinone impairs the degradation of I B α , and that the impairment of the degradation of I B α is the result of the inhibition of the interaction between VCP and the 26S proteasome by vesnarinone. These results suggest that vesnarinone suppresses NF B activation by inhibiting the VCP-dependent degradation of polyubiquitinated I B α , resulting in the suppression of tumor necrosis factor- α mRNA expression.
    Print ISSN: 0026-895X
    Electronic ISSN: 1521-0111
    Topics: Chemistry and Pharmacology , Medicine
    Published by The American Society for Pharmacology and Experimental Therapeutics (ASPET)
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  • 2
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    Role of High Endothelial Venule-Expressed Heparan Sulfate in Chemokine Presentation and Lymphocyte Homing [MOLECULAR AND STRUCTURAL IMMUNOLOGY] (2013)
    The American Association of Immunologists (AAI)
    Details
    Publication Date: 2013-06-22
    Description: Lymphocyte homing to peripheral lymph nodes (PLNs) is mediated by multistep interactions between lymphocytes and high endothelial venules (HEVs). Heparan sulfate (HS) has been implicated in the presentation of chemokines on the surface of HEVs during this process. However, it remains unclear whether this cell surface presentation is a prerequisite for lymphocyte homing. In this study, we generated conditional knockout (cKO) mice lacking Ext1 , which encodes a glycosyltransferase essential for HS synthesis, by crossing Ext1 flox/flox mice with GlcNAc6ST-2-Cre transgenic mice expressing Cre recombinase in HEVs. Immunohistochemical studies indicated that HS expression was specifically eliminated in PLN HEVs but retained in other blood vessels in the cKO mice. The accumulation of a major secondary lymphoid tissue chemokine, CCL21, on HEVs was also abrogated without affecting CCL21 mRNA levels, indicating that HS presents CCL21 on HEVs in vivo. Notably, a short-term lymphocyte homing assay indicated that lymphocyte homing to PLNs was diminished in the cKO mice by 30–40%. Consistent with this result, contact hypersensitivity responses were also diminished in the cKO mice. The residual lymphocyte homing to PLNs in the cKO mice was dependent on pertussis toxin–sensitive G i protein signaling, in which lysophosphatidic acid–mediated signaling was partly involved. These results suggest that chemokine presentation by HS on the surface of HEVs facilitates but is not absolutely required for lymphocyte homing.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
    Published by The American Association of Immunologists (AAI)
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  • 3
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    Salicylic Acid Induces Mitochondrial Injury by Inhibiting Ferrochelatase Heme Biosynthesis Activity [Articles] (2013)
    The American Society for Pharmacology and Experimental Therapeutics (ASPET)
    Details
    Publication Date: 2013-11-05
    Description: Salicylic acid is a classic nonsteroidal anti-inflammatory drug. Although salicylic acid also induces mitochondrial injury, the mechanism of its antimitochondrial activity is not well understood. In this study, by using a one-step affinity purification scheme with salicylic acid–immobilized beads, ferrochelatase (FECH), a homodimeric enzyme involved in heme biosynthesis in mitochondria, was identified as a new molecular target of salicylic acid. Moreover, the cocrystal structure of the FECH–salicylic acid complex was determined. Structural and biochemical studies showed that salicylic acid binds to the dimer interface of FECH in two possible orientations and inhibits its enzymatic activity. Mutational analysis confirmed that Trp301 and Leu311, hydrophobic amino acid residues located at the dimer interface, are directly involved in salicylic acid binding. On a gel filtration column, salicylic acid caused a shift in the elution profile of FECH, indicating that its conformational change is induced by salicylic acid binding. In cultured human cells, salicylic acid treatment or FECH knockdown inhibited heme synthesis, whereas salicylic acid did not exert its inhibitory effect in FECH knockdown cells. Concordantly, salicylic acid treatment or FECH knockdown inhibited heme synthesis in zebrafish embryos. Strikingly, the salicylic acid–induced effect in zebrafish was partially rescued by FECH overexpression. Taken together, these findings illustrate that FECH is responsible for salicylic acid–induced inhibition of heme synthesis, which may contribute to its antimitochondrial and anti-inflammatory function. This study establishes a novel aspect of the complex pharmacological effects of salicylic acid.
    Print ISSN: 0026-895X
    Electronic ISSN: 1521-0111
    Topics: Chemistry and Pharmacology , Medicine
    Published by The American Society for Pharmacology and Experimental Therapeutics (ASPET)
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  • 4
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    Pulmonary Epithelial TLR4 Activation Leads to Lung Injury in Neonatal Necrotizing Enterocolitis [INNATE IMMUNITY AND INFLAMMATION] (2016)
    The American Association of Immunologists (AAI)
    Details
    Publication Date: 2016-07-19
    Description: We seek to define the mechanisms leading to the development of lung disease in the setting of neonatal necrotizing enterocolitis (NEC), a life-threatening gastrointestinal disease of premature infants characterized by the sudden onset of intestinal necrosis. NEC development in mice requires activation of the LPS receptor TLR4 on the intestinal epithelium, through its effects on modulating epithelial injury and repair. Although NEC-associated lung injury is more severe than the lung injury that occurs in premature infants without NEC, the mechanisms leading to its development remain unknown. In this study, we now show that TLR4 expression in the lung gradually increases during postnatal development, and that mice and humans with NEC-associated lung inflammation express higher levels of pulmonary TLR4 than do age-matched controls. NEC in wild-type newborn mice resulted in significant pulmonary injury that was prevented by deletion of TLR4 from the pulmonary epithelium, indicating a role for pulmonary TLR4 in lung injury development. Mechanistically, intestinal epithelial TLR4 activation induced high-mobility group box 1 release from the intestine, which activated pulmonary epithelial TLR4, leading to the induction of the neutrophil recruiting CXCL5 and the influx of proinflammatory neutrophils to the lung. Strikingly, the aerosolized administration of a novel carbohydrate TLR4 inhibitor prevented CXCL5 upregulation and blocked NEC-induced lung injury in mice. These findings illustrate the critical role of pulmonary TLR4 in the development of NEC-associated lung injury, and they suggest that inhibition of this innate immune receptor in the neonatal lung may prevent this devastating complication of NEC.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
    Published by The American Association of Immunologists (AAI)
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  • 5
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    Vitamin K2 Covalently Binds to Bak and Induces Bak-Mediated Apoptosis [Articles] (2013)
    The American Society for Pharmacology and Experimental Therapeutics (ASPET)
    Details
    Publication Date: 2013-02-19
    Description: Vitamin K2 (VK2, menaquinone) is known to have anticancer activity in vitro and in vivo. Although its effect is thought to be mediated, at least in part, by the induction of apoptosis, the underlying molecular mechanism remains elusive. Here, we identified Bcl-2 antagonist killer 1 (Bak) as a molecular target of VK2-induced apoptosis. VK2 directly interacts with Bak and induces mitochondrial-mediated apoptosis. Although Bak and Bcl-2-associated X protein (Bax), another member of the Bcl-2 family, are generally thought to be functionally redundant, only Bak is necessary and sufficient for VK2-induced cytochrome c (cyt c) release and cell death. Moreover, VK2-2,3 epoxide, an intracellular metabolite of VK2, was shown to covalently bind to the cysteine-166 residue of Bak. Several lines of evidence suggested that the covalent attachment of VK2 is critical for apoptosis induction. Thus this study reveals a specific role for Bak in mitochondria-mediated apoptosis. This study also provides insight into the anticancer effects of VK2 and suggests that Bak may be a potential target of cancer therapy.
    Print ISSN: 0026-895X
    Electronic ISSN: 1521-0111
    Topics: Chemistry and Pharmacology , Medicine
    Published by The American Society for Pharmacology and Experimental Therapeutics (ASPET)
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  • 6
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    Intestinal Epithelial TLR-4 Activation Is Required for the Development of Acute Lung Injury after Trauma/Hemorrhagic Shock via the Release of HMGB1 from the Gut [INNATE IMMUNITY AND INFLAMMATION] (2015)
    The American Association of Immunologists (AAI)
    Details
    Publication Date: 2015-05-02
    Description: The mechanisms that lead to the development of remote lung injury after trauma remain unknown, although a central role for the gut in the induction of lung injury has been postulated. We hypothesized that the development of remote lung injury after trauma/hemorrhagic shock requires activation of TLR4 in the intestinal epithelium, and we sought to determine the mechanisms involved. We show that trauma/hemorrhagic shock caused lung injury in wild-type mice, but not in mice that lack TLR4 in the intestinal epithelium, confirming the importance of intestinal TLR4 activation in the process. Activation of intestinal TLR4 after trauma led to increased endoplasmic reticulum (ER) stress, enterocyte apoptosis, and the release of circulating HMGB1, whereas inhibition of ER stress attenuated apoptosis, reduced circulating HMGB1, and decreased lung injury severity. Neutralization of circulating HMGB1 led to reduced severity of lung injury after trauma, and mice that lack HMGB1 in the intestinal epithelium were protected from the development of lung injury, confirming the importance of the intestine as the source of HMGB1, whose release of HMGB1 induced a rapid protein kinase C –mediated internalization of surface tight junctions in the pulmonary epithelium. Strikingly, the use of a novel small-molecule TLR4 inhibitor reduced intestinal ER stress, decreased circulating HMGB1, and preserved lung architecture after trauma. Thus, intestinal epithelial TLR4 activation leads to HMGB1 release from the gut and the development of lung injury, whereas strategies that block upstream TLR4 signaling may offer pulmonary protective strategies after trauma.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
    Published by The American Association of Immunologists (AAI)
    Location Call Number Limitation Availability
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