Browsing by Subject "Platelet-activating factor"

Now showing 1 - 7 of 7
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    Acute Ethanol Exposure Augments Low-Dose UVB-Mediated Systemic Immunosuppression via Enhanced Production of Platelet-Activating Factor Receptor Agonists
    (Elsevier, 2019-01-22) Travers, Jeffrey B.; Weyerbacher, Jonathan; Ocana, Jesus A.; Borchers, Christina; Rapp, Christine M.; Sahu, Ravi P.; Dermatology, School of Medicine
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    Cigarette smoke exposure inhibits contact hypersensitivity via the generation of platelet activating factor agonists
    (Oxford University Press, 2013) Sahu, Ravi P.; Petrache, Irina; Van Demark, Mary J.; Rashid, Badri M.; Ocana, Jesus A.; Tang, Yuxuan; Yi, Qiaofang; Turner, Matthew J.; Konger, Raymond L.; Travers, Jeffrey B.; Dermatology, School of Medicine
    Previous studies have established that pro-oxidative stressors suppress host immunity because of their ability to generate oxidized lipids with platelet-activating factor receptor (PAF-R) agonist activity. Although exposure to the pro-oxidative stressor cigarette smoke (CS) is known to exert immunomodulatory effects, little is known regarding the role of PAF in these events. The current studies sought to determine the role of PAF-R signaling in CS-mediated immunomodulatory effects. We demonstrate that CS exposure induces the generation of a transient PAF-R agonistic activity in the blood of mice. CS exposure inhibits contact hypersensitivity in a PAF-R-dependent manner as PAF-R-deficient mice were resistant to these effects. Blocking PAF-R agonist production either by systemic antioxidants or treatment with serum PAF-acetyl hydrolase enzyme blocked both the CS-mediated generation of PAF-R agonists and PAF-R-dependent inhibition of contact hypersensitivity (CHS) reactions, indicating a role for oxidized glycerophosphocholines with PAF-R agonistic activity in this process. In addition, cyclooxygenase-2 inhibition did not block PAF-R agonist production but prevented CS-induced inhibition of CHS. This suggests that cyclooxygenase-2 acts downstream of the PAF-R in mediating CS-induced systemic immunosuppression. Moreover, CS exposure induced a significant increase in the expression of the regulatory T cell reporter gene in Foxp3(EGFP) mice but not in Foxp3(EGFP) mice on a PAF-R-deficient background. Finally, regulatory T cell depletion via anti-CD25 Abs blocked CS-mediated inhibition of CHS, indicating the potential involvement of regulatory T cells in CS-mediated systemic immunosuppression. These studies provide the first evidence, to our knowledge, that the pro-oxidative stressor CS can modulate cutaneous immunity via the generation of PAF-R agonists produced through lipid oxidation.
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    Cigarette smoke exposure mediated generation of Platelet-activating factor agonists induces systemic immunosuppression
    (Office of the Vice Chancellor for Research, 2012-04-13) Sahu, Ravi P.; Turner, Matthew J.; Konger, Raymond L.; Travers, Jeffrey B.
    The ubiquitous environmental pollutant cigarette smoke (CS) is known to exert immodulatory effects. CS also acts as a potent pro-oxidative stressor. Several studies including ours have characterized the importance of various pro-oxidative stressors including UVB to inhibit host immunity and an importance of the platelet-activating factor (1-alkyl-2-acetyl-glycerophosphocholine; PAF), a potent lipid mediator in this process. PAF is produced enzymatically in a tightly-controlled process. In addition, oxidative stressors can act directly on glycerophosphocholines (GPC) to produce oxidized GPC which are potent PAF-R agonists. The present studies employed model systems consisting of PAF-receptor (PAF-R)-expressing (KBP) and–deficient (KBM) cells and mice (wild type [WT] and Pafr-/-) to determine whether CS exposure could generate PAF-R agonists in blood and whether it could suppress contact hypersensitivity reactions in a PAF-R-dependent manner. We show that lipid extracts derived from the blood of CS-treated WT mice resulted in immediate intracellular calcium (Ca2+2+mice. This inhibitory effect of CS in WT mice were similar to those induced by a PAF-R agonist, CPAF or histamine. Furthermore, this inhibition of CHS by CS in WT mice was blocked by antioxidants vitamin C and N-acetyl cysteine. These findings indicate that CS exposure induces systemic immunosuppression in a PAF-R-dependent manner. These studies provide the first evidence that the pro-oxidative stressor CS can modulate cutaneous immunity via the generation of PAF agonists through lipid oxidation.) mobilization response only in KBP cells. However, no Camobilization response was detected with lipid extracts from non-smoked (sham) mice both in KBP and KBM cells. In addition, lipid extracts only from CS-treated mice induced an increase in IL-8 secretion in KBP cells indicating that CS generates systemic PAF-R agonists. CS exposure also inhibited contact hypersensitivity to the allergen dinitrofluorobenzene (DNFB) selectively in WT but not inPafr-/-
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    Mast cells mediate systemic immunosuppression induced by platelet-activating factor via histamine and cyclooxygenase-2 dependent mechanisms
    (2016-05-02) Ocaña, Jesus Alejandro; Safa, Ahmad R.; Travers, Jeffrey B.; Kaplan, Mark H.; Lu, Tao; Zhang, Jian-Ting
    Platelet-activating Factor (PAF) stimulates various cell types by the activation of the G-protein coupled PAF-receptor (PAFR). Systemic PAFR activation induces an acute pro-inflammatory response, as well as delayed systemic immunosuppressive effects in vivo. De novo enzymatic PAF synthesis and degradation are closely regulated, but oxidative stressors, such as UVB, and cigarette smoke, can generate PAF-like species via the oxidation of membrane lipids in an unregulated process. Mast cells (MCs) and the PAFR have been shown to be necessary to mediate the resulting systemic immune suppression from oxidative stressors. The work herein implicates pro-oxidative chemotherapeutics, such as melphalan and etoposide, in mediating augmentation in tumor growth by inducing the generation of PAFR agonists via the oxidation of membrane lipids. This work also demonstrates the role of MCs and MC-released mediators in PAFR systemic immunosuppression. Through a contact hypersensitivity (CHS) model, the MC PAFR was found to be necessary and sufficient for PAF to mediate systemic immunosuppression. Additionally, activation of the MC PAFR seems to induce MC histamine and prostaglandin E2 release. Furthermore, by transplanting histamine- or COX-2-deficient MCs into MC-deficient mice, MC-derived histamine and prostaglandin release were found to be necessary for PAF to induce systemic immunosuppression. Lastly, we have evidence to suggest that prostaglandin release modulates MC migration to draining lymph nodes, a process necessary to promote immunosuppression. These studies fit with the hypothesis that MC PAFR activation mediates PAFR systemic immunosuppression in part by histamine and prostaglandin release.
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    Platelet-Activating Factor-Induced Reduction in Contact Hypersensitivity Responses Is Mediated by Mast Cells via Cyclooxygenase-2-Dependent Mechanisms
    (American Association of Immunologists, 2018-06-15) Ocana, Jesus A.; Romer, Eric; Sahu, Ravi; Pawelzik, Sven-Christian; FitzGerald, Garret A.; Kaplan, Mark H.; Travers, Jeffrey B.; Pharmacology and Toxicology, School of Medicine
    Platelet-activating factor (PAF) stimulates numerous cell types via activation of the G protein-coupled PAF receptor (PAFR). PAFR activation not only induces acute proinflammatory responses, but it also induces delayed systemic immunosuppressive effects by modulating host immunity. Although enzymatic synthesis and degradation of PAF are tightly regulated, oxidative stressors, such as UVB, chemotherapy, and cigarette smoke, can generate PAF and PAF-like molecules in an unregulated fashion via the oxidation of membrane phospholipids. Recent studies have demonstrated the relevance of the mast cell (MC) PAFR in PAFR-induced systemic immunosuppression. The current study was designed to determine the exact mechanisms and mediators involved in MC PAFR-mediated systemic immunosuppression. By using a contact hypersensitivity model, the MC PAFR was not only found to be necessary, but also sufficient to mediate the immunosuppressive effects of systemic PAF. Furthermore, activation of the MC PAFR induces MC-derived histamine and PGE2 release. Importantly, PAFR-mediated systemic immunosuppression was defective in mice that lacked MCs, or in MC-deficient mice transplanted with histidine decarboxylase- or cyclooxygenase-2-deficient MCs. Lastly, it was found that PGs could modulate MC migration to draining lymph nodes. These results support the hypothesis that MC PAFR activation promotes the immunosuppressive effects of PAF in part through histamine- and PGE2-dependent mechanisms.
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    Platelet-Activating Factor-Receptor and Tumor Immunity
    (JSciMed Central, 2014) Sahu, Ravi P.; Konger, Raymond L.; Travers, Jeffrey B.; Department of Pathology and Laboratory Medicine, IU School of Medicine
    First described in 1972 by Benveniste and colleagues, platelet-activating factor (PAF) remains one of the potent phospholipid known to date. The role of PAF produced enzymatically in mediating diverse biological and pathophysiological processes including inflammatory and allergic diseases and cancers in response to various stimuli has been extensively studied. However, little is known about the role of non-enzymatically-generated PAF-like lipids produced in response to pro-oxidative stressors, particularly in modulating the host immune responses to tumor immunity, which is the focus of this review.
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    Radiation therapy generates platelet-activating factor agonists
    (Impact Journals, 2016-04-12) Sahu, Ravi P.; Harrison, Kathleen A.; Weyerbacher, Jonathan; Murphy, Robert C.; Konger, Raymond L.; Garrett, Joy Elizabeth; Chin-Sinex, Helen Jan; Johnston II., Michael Edward; Dynlacht, Joseph R.; Mendonca, Marc; McMullen, Kevin; Li, Gengxin; Spandau, Dan F.; Travers, Jeffrey B.; Department of Dermatology, IU School of Medicine
    Pro-oxidative stressors can suppress host immunity due to their ability to generate oxidized lipid agonists of the platelet-activating factor-receptor (PAF-R). As radiation therapy also induces reactive oxygen species, the present studies were designed to define whether ionizing radiation could generate PAF-R agonists and if these lipids could subvert host immunity. We demonstrate that radiation exposure of multiple tumor cell lines in-vitro, tumors in-vivo, and human subjects undergoing radiation therapy for skin tumors all generate PAF-R agonists. Structural characterization of radiation-induced PAF-R agonistic activity revealed PAF and multiple oxidized glycerophosphocholines that are produced non-enzymatically. In a murine melanoma tumor model, irradiation of one tumor augmented the growth of the other (non-treated) tumor in a PAF-R-dependent process blocked by a cyclooxygenase-2 inhibitor. These results indicate a novel pathway by which PAF-R agonists produced as a byproduct of radiation therapy could result in tumor treatment failure, and offer important insights into potential therapeutic strategies that could improve the overall antitumor effectiveness of radiation therapy regimens.