scholarly journals Platelet-activating Factor, a Molecular Sensor for Cellular Damage, Activates Systemic Immune Suppression

2002 ◽  
Vol 195 (2) ◽  
pp. 171-179 ◽  
Author(s):  
Jeffrey P. Walterscheid ◽  
Stephen E. Ullrich ◽  
Dat X. Nghiem
Keyword(s):  
Skin Cancer ◽  
Uv Radiation ◽  
Immune Suppression ◽  
Critical Role ◽  
Platelet Activating Factor ◽  
Cellular Damage ◽  
Uv Exposure ◽  
Delayed Type Hypersensitivity ◽  
Lipid Mediator ◽  
Paf Receptor

Ultraviolet (UV) radiation plays a critical role in the induction of nonmelanoma skin cancer. UV radiation is also immune suppressive, and the immune suppression induced by UV irradiation has been identified as a major risk factor for skin cancer induction. Previously, we showed that UV exposure activates a cytokine cascade involving prostaglandin (PG)E2, interleukin (IL)-4, and IL-10 that induces immune suppression. However, the earliest molecular events that occur immediately after UV exposure, especially those upstream of PGE2, are not well defined. UV-irradiated keratinocytes secrete the inflammatory phospholipid mediator, platelet-activating factor (PAF). Because PAF upregulates the production of immunomodulatory compounds, including PGE2, we tested the hypothesis that UV-induced PAF activates cytokine production and initiates UV-induced immune suppression. Both UV and PAF activated cyclooxygenase (COX)-2 and IL-10 reporter gene construct transcription. PAF mimicked the effects of UV in vivo and suppressed delayed-type hypersensitivity (DTH). Furthermore, immune suppression was blocked when UV-irradiated mice were injected with PAF receptor antagonists. In addition to the well-known role of PAF as a proinflammatory lipid mediator, we propose that the PAF receptor senses cellular damage through the recognition of PAF and/or PAF-like molecules, such as oxidized phosphatidylcholine, which activates cytokine transcription and induces systemic immune suppression.

scholarly journals A Critical Role for Fas Ligand in the Active Suppression of Systemic Immune Responses by Ultraviolet Radiation

1999 ◽  
Vol 189 (8) ◽  
pp. 1285-1294 ◽  
Author(s):  
Laurie L. Hill ◽  
Vijay K. Shreedhar ◽  
Margaret L. Kripke ◽  
Laurie B. Owen-Schaub
Keyword(s):  
Dna Damage ◽  
Immune Responses ◽  
Immune Suppression ◽  
Fas Ligand ◽  
Critical Role ◽  
Cell Activity ◽  
Contact Hypersensitivity ◽  
Delayed Type Hypersensitivity ◽  
Intact Cells

Induction of antigen-specific suppression elicited by environmental insults, such as ultraviolet (UV)-B radiation in sunlight, can inhibit an effective immune response in vivo and may contribute to the outgrowth of UV-induced skin cancer. Although UV-induced DNA damage is known to be an initiating event in the immune suppression of most antigen responses, the underlying mechanism(s) of such suppression remain undefined. In this report, we document that Fas ligand (FasL) is critical for UV-induced systemic immune suppression. Normal mice acutely exposed to UV exhibit a profound suppression of both contact hypersensitivity and delayed type hypersensitivity (DTH) reactions and the development of transferable antigen-specific suppressor cells. FasL-deficient mice exposed to UV lack both transferable suppressor cell activity and primary suppression to all antigens tested, with the exception of the DTH response to allogeneic spleen cells. Interestingly, suppression of this response is also known to occur independently of UV-induced DNA damage. Delivery of alloantigen as protein, rather than intact cells, restored the requirement for FasL in UV-induced immune suppression of this response. These results substantiate that FasL/Fas interactions are essential for systemic UV-induced suppression of immune responses that involve host antigen presentation and suggest an interrelationship between UV-induced DNA damage and FasL in this phenomenon. Collectively, our results suggest a model whereby UV-induced DNA damage disarms the immune system in a manner similar to that observed in immunologically privileged sites.

Skin Cancer

2018 ◽  
Author(s):  
Adèle C. Green ◽  
Catherine M. Olsen ◽  
David J. Hunter
Keyword(s):  
Skin Cancer ◽  
Cell Carcinoma ◽  
Uv Radiation ◽  
Molecular Mechanisms ◽  
Sun Exposure ◽  
Uv Exposure ◽  
Skin Cancers ◽  
Cells Of Origin ◽  
Solar Ultraviolet

Skin cancer is one of the few types of cancer for which exposure to the major carcinogen, solar ultraviolet (UV) radiation, is strongly implicated on the basis of descriptive epidemiologic data alone. There are three major forms of skin cancer considered in this chapter—melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC)—and each appears to have different causal relations to the pattern and total amount of sun exposure. High-intensity UV exposure and long-term UV exposure appear to be involved differentially in the various skin cancers and their subtypes. Underlying molecular mechanisms are becoming better understood, though many aspects like the cells of origin and the exact roles of intermediate lesions like actinic keratoses and nevi remain unclear. Because exposure of skin to UV radiation is modifiable, skin cancers are substantially preventable.

Platelet activating factor receptor binding plays a critical role in jet fuel-induced immune suppression

2004 ◽  
Vol 195 (3) ◽  
pp. 331-338 ◽  
Author(s):  
Gerardo Ramos ◽  
Nasser Kazimi ◽  
Dat X Nghiem ◽  
Jeffrey P Walterscheid ◽  
Stephen E Ullrich
Keyword(s):  
Receptor Binding ◽  
Immune Suppression ◽  
Critical Role ◽  
Platelet Activating Factor ◽  
Jet Fuel ◽  
Platelet Activating Factor Receptor

scholarly journals Expression of human platelet-activating factor receptor gene in EoL-1 cells following butyrate-induced differentiation

1995 ◽  
Vol 305 (3) ◽  
pp. 829-835 ◽  
Author(s):  
T Izumi ◽  
S Kishimoto ◽  
T Takano ◽  
M Nakamura ◽  
Y Miyabe ◽  
...  
Keyword(s):  
Receptor Gene ◽  
Platelet Activating Factor ◽  
Allergic Inflammation ◽  
Genomic Analysis ◽  
Receptor Protein ◽  
Cell Surface Expression ◽  
Lipid Mediator ◽  
Mrna Accumulation ◽  
Leukaemia Cell Line ◽  
Paf Receptor

Platelet-activating factor (PAF) is a potent lipid mediator of allergic inflammation through its interaction with eosinophils. Expression of the PAF receptor is modulated by many agents, including those responsible for cell differentiation. We report here that differentiation of a human eosinophilic leukaemia cell line, EoL-1, by sodium n-butyrate is associated with induction of PAF receptor gene expression, as indicated by: PAF receptor mRNA accumulation; increases in the binding of [3H]WEB 2086, a PAF antagonist; analysis of cell-surface expression of PAF receptor protein using a monoclonal anti-(PAF receptor) antibody; and augmentation of PAF-induced increase in the intracellular concentration of calcium. Using cDNA cloning, the receptor expressed in EoL-1 cells was identified as ‘Transcript 1’, one of two transcripts which was previously reported from human genomic analysis (Mutoh, Bito, Minami, Nakamura, Honda, Izumi, Nakata, Kurachi, Terano and Shimizu (1993) FEBS Lett. 322, 129-134). The PAF-induced calcium response and phosphoinositide turnover were decreased by pertussis toxin (PTX) treatment, suggesting that these signals are coupled largely with PTX-sensitive G-protein(s) in EoL-1 cells. These systems may provide a useful experimental model with which to investigate the relationship between eosinophilic differentiation and PAF receptor induction, and the role of eosinophils in allergic responses.

scholarly journals New Insights Into the Pathologic Roles of the Platelet-Activating Factor System

2021 ◽  
Vol 12 ◽  
Author(s):  
Jeffrey B. Travers ◽  
Joyce G. Rohan ◽  
Ravi P. Sahu
Keyword(s):  
Cell Damage ◽  
Platelet Activating Factor ◽  
Receptor Activation ◽  
Lipid Mediator ◽  
Organ Systems ◽  
Paf Receptor ◽  
Bioactive Agents ◽  
Novel Therapeutic Strategies ◽  
Pathologic Processes ◽  
The Relationship

Described almost 50 years ago, the glycerophosphocholine lipid mediator Platelet-activating factor (PAF) has been implicated in many pathologic processes. Indeed, elevated levels of PAF can be measured in response to almost every type of pathology involving inflammation and cell damage/death. In this review, we provide evidence for PAF involvement in pathologic processes, with focus on cancer, the nervous system, and in photobiology. Importantly, recent insights into how PAF can generate and travel via bioactive extracellular vesicles such as microvesicle particles (MVP) are presented. What appears to be emerging from diverse pathologies in different organ systems is a common theme where pro-oxidative stressors generate oxidized glycerophosphocholines with PAF agonistic effects, which then trigger more enzymatic PAF synthesis via the PAF receptor. A downstream consequence of PAF receptor activation is the generation and release of MVP which provide a mechanism to transmit PAF as well as other bioactive agents. The knowledge gaps which when addressed could result in novel therapeutic strategies are also discussed. Taken together, an enhanced understanding of the PAF family of lipid mediators is essential in our improved comprehension of the relationship amongst the diverse cutaneous, cancerous, neurologic and systemic pathologic processes.

Abstract W P251: Novel Platelet-Activating Factor Receptor Antagonists Attenuate Brain Injury after Experimental Stroke

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Nicolas G Bazan ◽  
Larissa Khoutorova ◽  
Julio Alvarez-Builla ◽  
Ludmila Belayev
Keyword(s):  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Platelet Activating Factor ◽  
Synaptic Activity ◽  
Experimental Stroke ◽  
Vehicle Group ◽  
Receptor Antagonists ◽  
Physiological Variables ◽  
Paf Receptor

INTRODUCTION: Platelet-activating factor (PAF) is a bioactive phospholipid that regulates synaptic activity and when overproduced is a potent mediator of leukocyte functions, including platelet aggregation and inflammation. PAF concentration increases during ischemia-reperfusion and is a mediator of neurotoxicity. The inhibition of this process plays a critical role in neuronal survival. We synthesized various analogues and identified them as PAF receptor antagonists, which were then selected for in vivo experiments to evaluate anti-ischemic activity. METHODS: Physiologically controlled Sprague-Dawley rats received 2 h MCAo by poly-L-lysine-coated intraluminal suture. LAU compounds (LAU-0901, LAU-09015, LAU-09018, LAU-09019, LAU-09020 or LAU-09023; 30 mg/kg) or vehicle (45% cyclodextran) was administered IP at 2 h from onset of MCAo. Neurological status was evaluated during occlusion (at 60 min) and on day 1, 2, 3 and 7. Histopathology was carried out on day 7. RESULTS: Physiological variables were stable and showed no significant differences between groups. All LAU compounds significantly reduced the neurobehavioral deficit compared to the vehicle group, beginning from day 1 and persisting through the 7 day survival period. Histologically, the vehicle group showed large hemispheric infarcts with pan-necrosis. By contrast, LAU-treated rats showed preserved hemispheric structure and small subcortical infarcts. Treatment with LAU (LAU-0901, LAU-09015, LAU-09018, LAU-09019, or LAU-09023) significantly reduced total infarct volume compared to the vehicle group by 68%, 52%, 40%, 51% and 54%, respectively. CONCLUSION: Our results clearly indicate that novel LAU PAF receptor antagonists are highly neuroprotective on behavior and reduction of brain infarction in experimental stroke. These compounds may provide the basis for future therapeutics in patients suffering ischemic stroke.

Protein-tyrosine Kinase p72 syk Is Activated by Platelet Activating Factor in Platelets

1994 ◽  
Vol 72 (06) ◽  
pp. 937-941 ◽  
Author(s):  
Karim Rezaul ◽  
Shigeru Yanagi ◽  
Kiyonao Sada ◽  
Takanobu Taniguchi ◽  
Hirohei Yamamura
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Protein Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Critical Role ◽  
Platelet Activating Factor ◽  
Kinase Assay ◽  
Potential Candidate ◽  
Protein Tyrosine ◽  
Induced Aggregation

SummaryIt has been demonstrated that activation of platelets by platelet-activating factor (PAF) results in a dramatic increase in tyrosine phosphorylation of several cellular proteins. We report here that p72 syk is a potential candidate for the protein-tyrosine phosphorylation following PAF stimulation in porcine platelets. Immunoprecipitation kinase assay revealed that PAF stimulation resulted in a rapid activation of p72 syk which peaked at 10 s. The level of activation was found to be dose dependent and could be completely inhibited by the PAF receptor antagonist, CV3988. Phosphorylation at the tyrosine residues of p72 syk coincided with activation of yllsyk. Pretreatment of platelets with aspirin and apyrase did not affect PAF induced activation of p72 syk .Furthermore, genistein, a potent protein-tyrosine-kinase inhibitor, diminished PAF-induced p72 syk activation and Ca2+ mobilization as well as platelet aggregation. These results suggest that p72 syk may play a critical role in PAF-induced aggregation, possibly through regulation of Ca2+ mobilization.

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