Platelet-Activating Factor-Induced Reduction in Contact Hypersensitivity Responses Is Mediated by Mast Cells via Cyclooxygenase-2-Dependent Mechanisms

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

Treatment of estrogen-induced dermatitis with omalizumab

In 1945, Drs Bernhard Zondek and Yehuda Bromberg demonstrated intradermal treatment with estrone and estradiol benzoate induced urticarial lesions in some patients.1 Fifty years later, Shelley et al,2 who introduced the concept of progesterone dermatitis several decades prior, defined estrogen dermatitis based on studies of 7 women with premenstrual flares of skin eruptions including papulovesicular, urticarial, or eczematous lesions or generalized pruritus. Previously described therapies for estrogen dermatitis include estrogen desensitization, tamoxifen, leuprolide, and oophorectomy.3 Here we report a case of estrogen-induced dermatitis successfully treated with omalizumab

Epidermal PPARγ influences subcutaneous tumor growth and acts through TNF-α to regulate contact hypersensitivity and the acute photoresponse

It is known that ultraviolet B (UVB) induces PPARγ ligand formation while loss of murine epidermal PPARγ (Pparg-/-epi) promotes UVB-induced apoptosis, inflammation, and carcinogenesis. PPARγ is known to suppress tumor necrosis factor-α (TNF-α) production. TNF-α is also known to promote UVB-induced inflammation, apoptosis, and immunosuppression. We show that Pparg-/-epi mice exhibit increased baseline TNF-α expression. Neutralizing Abs to TNF-α block the increased photo-inflammation and photo-toxicity that is observed in Pparg-/-epi mouse skin. Interestingly, the increase in UVB-induced apoptosis in Pparg-/-epi mice is not accompanied by a change in cyclobutane pyrimidine dimer clearance or in mutation burden. This suggests that loss of epidermal PPARγ does not result in a significant alteration in DNA repair capacity. However, loss of epidermal PPARγ results in marked immunosuppression using a contact hypersensitivity (CHS) model. This impaired CHS response was significantly alleviated using neutralizing TNF-α antibodies or loss of germline Tnf. In addition, the PPARγ agonist rosiglitazone reversed UVB-induced systemic immunosuppression (UV-IS) as well as UV-induced growth of B16F10 melanoma tumor cells in syngeneic mice. Finally, increased B16F10 tumor growth was observed when injected subcutaneously into Pparg-/-epi mice. Thus, we provide novel evidence that epidermal PPARγ is important for cutaneous immune function and the acute photoresponse

Platelet-activating Factor-receptor agonists generated by chemotherapy thwart host anti-tumor immunity

poster abstractPrevious studies have established that pro-oxidative stressors suppress host immunity due to their ability to generate oxidized glycerophosphocholine (Ox-GPC) lipids with Platelet-activating Factor-receptor (PAF-R) agonist activity. Because many chemotherapeutic agents also induce reactive oxygen species, the present studies were designed to define if chemotherapeutic agents could thwart host anti-tumor immunity against melanoma via PAF-R activation. We demonstrate that treatment of melanoma cell lines in vitro and tumors in vivo with chemotherapeutic agents generates PAF-R-agonists in a process blocked by antioxidants, indicating the involvement of non-enzymatic PAF-R-agonists in this event. In a model system consisting of implantation of two tumors, we show that intratumoral chemotherapy with melphalan or etoposide of one tumor significantly augments the growth of the other (untreated) tumor in wild-type but not PAF-R-deficient hosts. Chemotherapeutic agents-mediated PAF-R-dependent increased tumor growth is blocked by systemic administration of antioxidants and cyclooxygenase-2 inhibitors. In addition, depleting antibodies against regulatory T cells (Tregs) significantly attenuated chemotherapy-mediated growth of untreated tumors, suggesting the role of Tregs in this process. Moreover, using FoxP3EGFP transgenic mice, we show that COX-2 inhibitor blocked intratumoral Tregs, indicating that Tregs are downstream to COX-2. Furthermore, PAF-R agonists were identified in perfusates of patients undergoing isolated limb chemoperfusion for melanoma with melphalan chemotherapy. Finally, various novel Ox-GPCs are identified after chemotherapy by mass spectrometry. These findings provide evidence for a novel and previously unappreciated pathway by which Ox-GPC PAF-R agonists produced as a by-product of chemotherapy modulate tumor growth via the inhibition of anti-tumor immunity. These studies might explain some instances of chemotherapy treatment failure and offer insights into potential therapeutic strategies that could enhance the overall anti-tumor effectiveness of chemotherapy

Chemotherapeutic agents subvert tumor immunity by generating agonists of platelet-activating factor

Oxidative stress suppresses host immunity by generating oxidized lipid agonists of the platelet-activating factor receptor (PAF-R). Because many classical chemotherapeutic drugs induce reactive oxygen species (ROS), we investigated whether these drugs might subvert host immunity by activating PAF-R. Here, we show that PAF-R agonists are produced in melanoma cells by chemotherapy that is administered in vitro, in vivo, or in human subjects. Structural characterization of the PAF-R agonists induced revealed multiple oxidized glycerophosphocholines that are generated nonenzymatically. In a murine model of melanoma, chemotherapeutic administration could augment tumor growth by a PAF-R-dependent process that could be blocked by treatment with antioxidants or COX-2 inhibitors or by depletion of regulatory T cells. Our findings reveal how PAF-R agonists induced by chemotherapy treatment can promote treatment failure. Furthermore, they offer new insights into how to improve the efficacy of chemotherapy by blocking its heretofore unknown impact on PAF-R activation

Enhanced Platelet-activating Factor synthesis facilitates acute and delayed effects of ethanol intoxicated thermal burn injury

Thermal burn injuries in patients alcohol intoxicated result in greater morbidity and mortality. Murine models combining ethanol and localized thermal burn injury reproduce the systemic toxicity seen in human subjects, which consists of both acute systemic cytokine production with multiple organ dysfunction, as well as a delayed systemic immunosuppression. However, the exact mechanisms for these acute and delayed effects are unclear. These studies sought to define the role of the lipid mediator Platelet-activating factor (PAF) in the acute and delayed effects of intoxicated burn injury. Combining ethanol and thermal burn injury resulted in increased enzymatic PAF generation in a keratinocyte cell line in vitro, human skin explants ex vivo, as well as in murine skin in vivo. Further, the acute increase in inflammatory cytokines such as IL-6, and the systemic immunosuppressive effects of intoxicated thermal burn injury, were suppressed in mice lacking PAF receptors. Together, these studies provide a potential mechanism and novel treatment strategies for the augmented toxicity and immunosuppressive effects of thermal burn injury in the setting of acute ethanol exposure, which involves the pleotropic lipid mediator PAF

Platelet-Activating Factor-Induced Reduction in Contact Hypersensitivity Responses Is Mediated by Mast Cells via Cyclooxygenase-2-Dependent Mechanisms

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