Role of cytoplasmic tail phosphorylation sites of platelet-activating factor receptor in agonist-induced desensitization.

Although influenza infection alone may lead to pneumonia, secondary bacterial infections are a much more common cause of pneumonia. Streptococcus pneumoniae is the most frequently isolated causative pathogen during postinfluenza pneumonia. Considering that S. pneumoniae utilizes the platelet-activating factor receptor (PAFR) to invade the respiratory epithelium and that the PAFR is upregulated during viral infection, we here used PAFR gene-deficient (PAFR−/−) mice to determine the role of this receptor during postinfluenza pneumococcal pneumonia. Viral clearance was similar in wild-type and PAFR−/− mice, and influenza virus was completely removed from the lungs at the time mice were inoculated with S. pneumoniae ( day 14 after influenza infection). PAFR−/− mice displayed a significantly reduced bacterial outgrowth in their lungs, a diminished dissemination of the infection, and a prolonged survival. Pulmonary levels of IL-10 and KC were significantly lower in PAFR−/− mice, whereas IL-6 and TNF-α were only trendwise lower. These data indicate that the pneumococcus uses the PAFR leading to severe pneumonia in a host previously exposed to influenza A.

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Activation and Regulation of Platelet-Activating Factor Receptor: Role of Gi and Gq in Receptor-Mediated Chemotactic, Cytotoxic, and Cross-Regulatory Signals

The Journal of Immunology ◽

10.4049/jimmunol.177.5.3242 ◽

2006 ◽

Vol 177 (5) ◽

pp. 3242-3249 ◽

Cited By ~ 35

Author(s):

Stephan L. Brown ◽

Venkatakrishna R. Jala ◽

Sandeep K. Raghuwanshi ◽

Mohd W. Nasser ◽

Bodduluri Haribabu ◽

...

Keyword(s):

Platelet Activating Factor ◽

Platelet Activating Factor Receptor

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Immunomodulation by n-3- versus n-6-rich lipid emulsions in murine acute lung injury—Role of platelet-activating factor receptor

Critical Care Medicine ◽

10.1097/01.ccm.0000253811.74112.b6 ◽

2007 ◽

Vol 35 (2) ◽

pp. 544-554 ◽

Cited By ~ 22

Author(s):

Martina Barbara Schaefer ◽

Juliane Ott ◽

Andrea Mohr ◽

Ming Hua Bi ◽

Andrea Grosz ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Platelet Activating Factor ◽

Lipid Emulsions ◽

Platelet Activating Factor Receptor

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Systemic Platelet-Activating Factor-Receptor Agonism Enhances Non-Melanoma Skin Cancer Growth

International Journal of Molecular Sciences ◽

10.3390/ijms19103109 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3109 ◽

Cited By ~ 2

Author(s):

Eric Romer ◽

Anita Thyagarajan ◽

Smita Krishnamurthy ◽

Christine Rapp ◽

Langni Liu ◽

...

Keyword(s):

Skin Cancer ◽

Platelet Activating Factor ◽

Chemical Carcinogenesis ◽

Melanocytic Nevus ◽

Non Melanoma Skin Cancer ◽

Cancer Models ◽

Platelet Activating Factor Receptor ◽

Melanoma Skin ◽

Topical Applications

Platelet-activating factor-receptor (PAF-R) agonists are pleiotropic lipid factors that influence multiple biological processes, including the induction and resolution of inflammation as well as immunosuppression. PAF-R agonists have been shown to modulate tumorigenesis and/or tumor growth in various skin cancer models by suppressing either cutaneous inflammation and/or anti-tumoral adaptive immunity. We have previously shown that a chronic systemic PAF-R agonist administration of mice enhances the growth of subcutaneously implanted melanoma tumors. Conversely, chronic topical applications of a PAF-R agonist suppressed non-melanoma skin cancer (NMSC) in a topical chemical carcinogenesis model (dimethylbenz[a]anthracene/phorbol 12-myristate 13-acetate (DMBA/PMA)) in-part via anti-inflammatory effects. These results indicate that the context of PAF-R agonist exposure via either chronic cutaneous or systemic administration, result in seemingly disparate effects on tumor promotion. To further dissect the contextual role of PAF-R agonism on tumorigenesis, we chronically administered systemic PAF-R agonist, carbamoyl-PAF (CPAF) to mice under a cutaneous chemical carcinogenesis protocol, recently characterized to initiate both NMSC and melanocytic nevus formation that can progress to malignant melanoma. Our results showed that while systemic CPAF did not modulate melanocytic nevus formation, it enhanced the growth of NMSC tumors.

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Role of PAF-acether in the mediation of pathophysiological responses to aggregated immunoglobulins. Studies with the platelet-activating factor receptor antagonist BN 52021

International Journal of Immunopharmacology ◽

10.1016/0192-0561(88)90121-x ◽

1988 ◽

Vol 10 (4) ◽

pp. 353-360 ◽

Cited By ~ 4

Author(s):

Sagrario Fernandez-Gallardo ◽

Ernesto Cano ◽

Pierre Braquet ◽

Mariano Sanchez Crespo

Keyword(s):

Receptor Antagonist ◽

Platelet Activating Factor ◽

Aggregated Immunoglobulins ◽

Platelet Activating Factor Receptor

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Essential role of platelet-activating factor receptor in the pathogenesis of Dengue virus infection

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0906467106 ◽

2009 ◽

Vol 106 (33) ◽

pp. 14138-14143 ◽

Cited By ~ 90

Author(s):

D. G. Souza ◽

C. T. Fagundes ◽

L. P. Sousa ◽

F. A. Amaral ◽

R. S. Souza ◽

...

Keyword(s):

Virus Infection ◽

Dengue Virus ◽

Essential Role ◽

Platelet Activating Factor ◽

Dengue Virus Infection ◽

Platelet Activating Factor Receptor

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Platelet-Activating Factor-Receptor Signaling Mediates Targeted Therapies-Induced Microvesicle Particles Release in Lung Cancer Cells

International Journal of Molecular Sciences ◽

10.3390/ijms21228517 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8517

Author(s):

Shreepa J. Chauhan ◽

Anita Thyagarajan ◽

Yanfang Chen ◽

Jeffrey B. Travers ◽

Ravi P. Sahu

Keyword(s):

Lung Cancer ◽

Cancer Cells ◽

Targeted Therapies ◽

Platelet Activating Factor ◽

Cellular Responses ◽

Therapeutic Agents ◽

Lung Cancer Cells ◽

Dependent Manner ◽

Platelet Activating Factor Receptor

Microvesicle particles (MVP) secreted by a variety of cell types in response to reactive oxygen species (ROS)-generating pro-oxidative stressors have been implicated in modifying the cellular responses including the sensitivity to therapeutic agents. Our previous studies have shown that expression of a G-protein coupled, platelet-activating factor-receptor (PAFR) pathway plays critical roles in pro-oxidative stressors-mediated cancer growth and MVP release. As most therapeutic agents act as pro-oxidative stressors, the current studies were designed to determine the role of the PAFR signaling in targeted therapies (i.e., gefitinib and erlotinib)-mediated MVP release and underlying mechanisms using PAFR-expressing human A549 and H1299 non-small cell lung cancer (NSCLC) cell lines. Our studies demonstrate that both gefitinib and erlotinib generate ROS in a dose-dependent manner in a process blocked by antioxidant and PAFR antagonist, verifying their pro-oxidative stressor’s ability, and the role of the PAFR in this effect. We observed that these targeted therapies induce MVP release in a dose- and time-dependent manner, similar to a PAFR-agonist, carbamoyl-PAF (CPAF), and PAFR-independent agonist, phorbol myristate acetate (PMA), used as positive controls. To confirm the PAFR dependency, we demonstrate that siRNA-mediated PAFR knockdown or PAFR antagonist significantly blocked only targeted therapies- and CPAF-mediated but not PMA-induced MVP release. The use of pharmacologic inhibitor strategy suggested the involvement of the lipid ceramide-generating enzyme, acid sphingomyelinase (aSMase) in MVP biogenesis, and observed that regardless of the stimuli used, aSMase inhibition significantly blocked MVP release. As mitogen-activated protein kinase (MAPK; ERK1/2 and p38) pathways crosstalk with PAFR, their inhibition also significantly attenuated targeted therapies-mediated MVP release. These findings indicate that PAFR signaling could be targeted to modify cellular responses of targeted therapies in lung cancer cells.

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