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Jeffrey P Walterscheid

Publications and source records attributed to Jeffrey P Walterscheid.

8 recordsLinked to original sources
PubMed2006

Cis-urocanic acid, a sunlight-induced immunosuppressive factor, activates immune suppression via the 5-HT2A receptor.

Exposure to UV radiation induces skin cancer and suppresses the immune response. To induce immune suppression, the electromagnetic energy of UV radiation must be absorbed by an epidermal photoreceptor and converted into a biologically recognizable signal. Two photoreceptors have been recognized: DNA and trans-urocanic acid (UCA). Trans-UCA is normally found in the outermost layer of skin and isomerizes to the cis isomer upon exposure to UV radiation. Although UCA was identified as a UV photoreceptor years ago, and many have documented its ability to induce immune suppression, its exact mode of action remains elusive. Particularly vexing has been the identity of the molecular pathway by which cis-UCA mediates immune suppression. Here we provide evidence that cis-UCA binds to the serotonin [5-hydroxytryptamine (5-HT)] receptor with relatively high affinity (Kd = 4.6 nM). Anti-cis-UCA antibody precipitates radiolabeled 5-HT, and the binding is inhibited by excess 5-HT and/or excess cis-UCA. Similarly, anti-5-HT antibody precipitates radiolabeled cis-UCA, and the binding is inhibited by excess 5-HT or excess cis-UCA. Calcium mobilization was activated when a mouse fibroblast line, stably transfected with the human 5-HT2A receptor, was treated with cis-UCA. Cis-UCA-induced calcium mobilization was blocked with a selective 5-HT2A receptor antagonist. UV- and cis-UCA-induced immune suppression was blocked by antiserotonin antibodies or by treating the mice with 5-HT2A receptor antagonists. Our findings identify cis-UCA as a serotonin receptor ligand and indicate that the immunosuppressive effects of cis-UCA and UV radiation are mediated by activation of the 5-HT2A receptor.

Animals↗
PubMed2006

Platelet-activating factor is crucial in psoralen and ultraviolet A-induced immune suppression, inflammation, and apoptosis.

Psoralen plus UVA (PUVA) is used as a very effective treatment modality for various diseases, including psoriasis and cutaneous T-cell lymphoma. PUVA-induced immune suppression and/or apoptosis are thought to be responsible for the therapeutic action. However, the molecular mechanisms by which PUVA acts are not well understood. We have previously identified platelet-activating factor (PAF), a potent phospholipid mediator, as a crucial substance triggering ultraviolet B radiation-induced immune suppression. In this study, we used PAF receptor knockout mice, a selective PAF receptor antagonist, a COX-2 inhibitor (presumably blocking downstream effects of PAF), and PAF-like molecules to test the role of PAF receptor binding in PUVA treatment. We found that activation of the PAF pathway is crucial for PUVA-induced immune suppression (as measured by suppression of delayed type hypersensitivity to Candida albicans) and that it plays a role in skin inflammation and apoptosis. Downstream of PAF, interleukin-10 was involved in PUVA-induced immune suppression but not inflammation. Better understanding of PUVA's mechanisms may offer the opportunity to dissect the therapeutic from the detrimental (ie, carcinogenic) effects and/or to develop new drugs (eg, using the PAF pathway) that act like PUVA but have fewer side effects.

Animals↗
PubMed2004

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

Applying military jet fuel (JP-8) or commercial jet fuel (Jet-A) to the skin of mice suppresses the immune response in a dose-dependent manner. The release of biological response modifiers, particularly prostaglandin E2 (PGE2), is a critical step in activating immune suppression. Previous studies have shown that injecting selective cyclooxygenase-2 inhibitors into jet fuel-treated mice blocks immune suppression. Because the inflammatory phospholipid mediator, platelet-activating factor (PAF), up-regulates cyclooxygenase-2 production and PGE2 synthesis by keratinocytes, we tested the hypothesis that PAF-receptor binding plays a role in jet fuel-induced immune suppression. Treating keratinocyte cultures with PAF and/or jet fuel (JP-8 and Jet-A) stimulates PGE2 secretion. Jet fuel-induced PGE2 production was suppressed by treating the keratinocytes with specific PAF-receptor antagonists. Injecting mice with PAF, or treating the skin of the mice with JP-8, or Jet-A, induced immune suppression. Jet fuel-induced immune suppression was blocked when the jet fuel-treated mice were injected with PAF-receptor antagonists before treatment. Jet fuel treatment has been reported to activate oxidative stress and treating the mice with anti-oxidants (Vitamins C, or E or beta-hydroxy toluene), before jet fuel application, interfered with immune suppression. These findings confirm previous studies showing that PAF-receptor binding can modulate immune function. Furthermore, they suggest that PAF-receptor binding may be an early event in the induction of immune suppression by immunotoxic environmental agents that target the skin.

Administration, Cutaneous↗
PubMed2002

Dermal application of jet fuel suppresses secondary immune reactions.

Applying military jet fuel (JP-8) to the skin of mice activates systemic immune suppression. In all of our previous experiments, JP-8 was applied to immunologically naïve mice. The effect of jet fuels on established immune reactions, such as immunological memory, is unknown. The focus of the experiments presented here was to test the hypothesis that jet fuel exposure [both JP-8 and commercial jet fuel (Jet-A)] suppresses established immune reactions. Mice were immunized with the opportunistic fungal pathogen Candida albicans and, at different times after immunization (10 to 30 days), various doses of undiluted JP-8 or Jet-A were applied to their skin. Both the elicitation of delayed-type hypersensitivity (DTH) (mice challenged 10 days after immunization) and immunological memory (mice challenged 30 days after immunization) were significantly suppressed in a dose-dependent manner. Dermal exposure to either multiple small doses (50 microl over 4 days) or a single large dose (approximately 200-300 microl) of JP-8 and/or Jet-A suppressed DTH to C. albicans. The mechanism by which dermal application of JP-8 and Jet-A suppresses immunological memory involves the release of immune biologic response modifiers. Blocking the production of prostaglandin E(2) by a selective cyclooxygenase-2 inhibitor (SC 236) significantly reversed jet fuel-induced suppression of immunologic memory. These findings indicate, for the first time, that dermal exposure to commercial jet fuel (Jet-A) suppresses the immune response. In addition, the data reported here expand on previous findings by suggesting that jet fuel exposure may depress the protective effect of prior vaccination.

Animals↗
PubMed2002

Platelet-activating factor, a molecular sensor for cellular damage, activates systemic immune suppression.

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)E(2), 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.

Animals↗
PubMed2002

Ultraviolet radiation-induced immunosuppression of delayed-type hypersensitivity in mice.

Ultraviolet (UV) radiation present in sunlight plays a critical role in the initiation and promotion of nonmelanoma skin carcinogenesis and immune suppression. The immune suppressive effects of UV have been identified as a risk factor for skin cancer induction. For these reasons, scientists have focused on elucidating the mechanisms of UV-induced immune suppression to better understand the pathogenesis of skin cancer induction. A hallmark of UV-induced immune suppression is the generation of antigen-specific suppressor T cells. These suppressor cells have been shown to suppress antitumor immunity as well as other cell-mediated responses such as delayed-type hypersensitivity (DTH) reactions. Due to the excessive cost and time involved in traditional UV carcinogenic experiments, scientists have opted to use UV-induced suppression of DTH reactions as a surrogate model. DTH has been, and continues to be, a widely used assay system to measure in vivo immune function. Although somewhat unsophisticated by today's standards, this assay has great advantages because it presents a fast, inexpensive, and reliable model system to help dissect the mechanisms involved in UV-induced immune suppression. Furthermore, the murine model of DTH enables scientists to perform additional procedures, such as adoptive transfer studies with suppressor T cells, which are currently unavailable with human subjects.

Adoptive Transfer↗
PubMed2002

Determining the role of cytokines in UV-induced immunomodulation.

Ultraviolet radiation exposure damages DNA and promotes the development of skin cancer. In addition, UV exposure suppresses the immune response. Although the mechanism by which epidermal exposure to UV induces systemic immune suppression is not fully understood, it is clear that cytokines are involved. Therefore, quantitative measurement of cytokines is a critical aspect of modern research techniques. Determining the level of synthesis and secretion of cytokines in vivo or in vitro can be achieved through several possible techniques, depending on the sampling size, its physical state, and the type of answers required to test the hypothesis. When studying transcriptional activation, the level of cytokine mRNA is often determined using reverse transcription polymerase chain reaction (RT-PCR), ribonuclease protection assay (RPA), or Northern blot. Quantitative determinations of specific protein levels require a capture ELISA. As with any analytical technique, there are compromises among expense of sensitivity, labor, and time. These methods are discussed as they pertain to surveying cytokine induction and their relative usefulness to the laboratory scientist.

Animals↗