Toxic interaction between Th2 cytokines and Staphylococcus aureus in atopic dermatitis

Patients with atopic dermatitis (AD) are commonly colonized/infected with Staphylococcus aureus, and this bacterium is known to worsen the dermatitis. In this issue, Brauweiler et al. demonstrate a newly discovered mechanism by which Th2 cytokines involved in AD augments the toxicity of the lytic staphylococcal protein alpha toxin. This review presents mechanisms by which Th2 cytokines may interact with S. aureus to the detriment of the dermatitis

Triamcinolone with Vitamin D Synergistic Efficacy in Psoriasis

Psoriasis is one of the most common skin conditions in the United States affecting more than 8 million people. High amounts of vitamin D has been shown to be effective in treatment of psoriasis. It also has a well-documented safety profile at the doses and duration that will be used during this study. Triamcinolone and other topical corticosteroids are considered a first line treatment for mild to moderate psoriasis with a well-documented safety profile. Individually both of these medications have shown effectiveness in the management and treatment of mild to moderate psoriasis. This study is designed to test whether a combination therapy of topical 0.1% triamcinolone with 40,000 IU vitamin D3 daily is effective in treating mild to moderate psoriasis

UVB-Induced Microvesicle Particle Release in Human Skin in vivo is Diminished Following Oral Vitamin C and E Antioxidant Administration

An important question in photobiology asks how Ultraviolet B (UVB, 290 – 320 nm) radiation, which mostly absorbs in the outer epidermis of skin, can generate a systemic response such as immunosuppression. Previous in vitro and ex vivo studies demonstrate UVB-dependent release of bioactive molecule-containing microvesicle particles (MVPs) from keratinocytes. Furthermore, MVP release is diminished upon antioxidant administration. The purpose of this study is to examine UVB-induced MVP release and antioxidant response in vivo. In this IRB-approved study, 8 male participants with Fitzpatrick type I or II skin were treated with 1000 J/m2 UVB irradiation to a 5 by 5 mm area of volar forearm skin. 4 hours later, punch biopsies and erythema measurements were performed. This procedure was repeated 8 days later following a course of oral antioxidants (vitamin C 2g/day, vitamin E 1000IU/day). On average, tissue MVP release increased 1.8-fold (+/- 0.31, P = 0.02) following UVB treatment. Following a course of oral antioxidants, the average UVB-induced tissue MVP release did not differ from the control (0.9-fold +/- 0.13, P = 0.23). There was no significant change in UVB-induced erythema between pre- and post-antioxidant administration. These studies suggest that UVB-MVP are dependent upon reactive oxygen species

How Wounding via Lasers Has Potential Photocarcinogenic Preventative Effects via Dermal Remodeling

As the incidence of non-melanoma skin cancer (NMSC) is increasing, there is a growing need to identify effective preventive strategies. A recently proposed hypothesis states that NMSC photocarcinogenesis is tightly linked to insufficient insulin growth factor-1 expression by agglomerated senescent fibroblasts in geriatric dermis. This paucity of IGF-1 expression in senile skin allows basal keratinocytes to mitotically propagate their UVB-altered genome and potentially initiate an actinic neoplasm. Here we review the role of the dermal microenvironment in NMSC pathogenesis, describe the impact of fibroblast senescence on this process and discuss how laser-induced dermal wounding can be effectively used to prevent NMSC development in geriatric patients

The IUPUI Signature Center for Atopic Dermatitis

poster abstractAtopic dermatitis is a chronic inflammatory skin disease characterized by dry skin, hypersensitivity to irritants and allergens, and significant pruritus. Atopic dermatitis is commonly associated with other atopic diseases including asthma, allergic rhinitis, and gastrointestinal disorders including eosinophilic esophagitis. Though a very common disease, there exists much misinformation and controversy/conflict in both the lay and medical communities about its pathogenesis and treatment, resulting in suboptimal care for the atopic dermatitis patient. Thus, education of both clinicians and lay public is needed. Inasmuch as atopic dermatitis is considered a systemic disorder, the optimal management should entail a multidisciplinary approach. Finally, research into the mechanisms by which atopic dermatitis occurs is needed to improve treatment of this common and quite debilitating disorder. The objective of the IUPUI Signature Center for Atopic Dermatitis is to provide optimal patient care, education and research in atopic dermatitis for the citizens of the state of Indiana. The Atopic Dermatitis has three separate components. First, we have developed an Atopic Dermatitis Working Group (ADWG) consisting of clinicians and scientists who meet on a monthly basis to disseminate information about research ideas/trials, and discuss topics and present difficult patients. Second, we have developed a monthly multidisciplinary AD clinic which has attracted the most challenging AD patients. Finally, we have developed infrastructure to assist in clinical and basic science research projects involving AD. Altogether, the IUPUI Signature Center for AD has been very successful as measured by the numbers of clinicians, researchers and patients who have been impacted by its presence

Platelet-Activating Factor-Receptor and Tumor Immunity

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

Insulin-like Growth Factor 1 Receptor Signaling Is Required for Optimal ATR-CHK1 Kinase Signaling in Ultraviolet B (UVB)-irradiated Human Keratinocytes

UVB wavelengths of light induce the formation of photoproducts in DNA that are potentially mutagenic if not properly removed by the nucleotide excision repair machinery. As an additional mechanism to minimize the risk of mutagenesis, UVB-irradiated cells also activate a checkpoint signaling cascade mediated by the ATM and Rad3-related (ATR) and checkpoint kinase 1 (CHK1) kinases to transiently suppress DNA synthesis and cell cycle progression. Given that keratinocytes in geriatric skin display reduced activation of the insulin-like growth factor 1 receptor (IGF-1R) and alterations in DNA repair rate, apoptosis, and senescence following UVB exposure, here we used cultured human keratinocytes in vitro and skin explants ex vivo to examine how IGF-1R activation status affects ATR-CHK1 kinase signaling and the inhibition of DNA replication following UVB irradiation. We find that disruption of IGF-1R signaling with small-molecule inhibitors or IGF-1 withdrawal partially abrogates both the phosphorylation and activation of CHK1 by ATR and the accompanying inhibition of chromosomal DNA synthesis in UVB-irradiated keratinocytes. A critical protein factor that mediates both ATR-CHK1 signaling and nucleotide excision repair is replication protein A, and we find that its accumulation on UVB-damaged chromatin is partially attenuated in cells with an inactive IGF-1R. These results indicate that mutagenesis and skin carcinogenesis in IGF-1-deficient geriatric skin may be caused by defects in multiple cellular responses to UVB-induced DNA damage, including through a failure to properly suppress DNA synthesis on UVB-damaged DNA templates

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

Cigarette smoke exposure mediated generation of Platelet-activating factor agonists induces systemic immunosuppression

poster abstractThe 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-/