A combination of three antioxidants decreases the impact of rural particulate pollution in Normal human keratinocytes.

Objective: It is well established that exposure of human skin to airborne pollution, particularly in the form of particulate matter sized 2.5 μm (PM ), is associated with oxidative stress, DNA damage and inflammation, leading to premature signs of skin aging. Because much of the damage results from oxidative stress, we examined the effects of a topical composition containing three antioxidants in an in vitro model system to assess the potential for amelioration of premature aging.

Selective stimulation of IL-4 receptor on smooth muscle induces airway hyperresponsiveness in mice.

Production of the cytokines IL-4 and IL-13 is increased in both human asthma and mouse asthma models, and Stat6 activation by the common IL-4/IL-13R drives most mouse model pathophysiology, including airway hyperresponsiveness (AHR). However, the precise cellular mechanisms through which IL-4Rα induces AHR remain unclear. Overzealous bronchial smooth muscle constriction is thought to underlie AHR in human asthma, but the smooth muscle contribution to AHR has never been directly assessed.

Dendritic cells and skin sensitization: biological roles and uses in hazard identification.

Recent advances have been made in our understanding of the roles played by cutaneous dendritic cells (DCs) in the induction of contact allergy. A number of associated changes in epidermal Langerhans cell phenotype and function required for effective skin sensitization are providing the foundations for the development of cellular assays (using DC and DC-like cells) for skin sensitization hazard identification. These alternative approaches to the identification and characterization of skin sensitizing chemicals were the focus of a Workshop entitled "Dendritic Cells and Skin Sensitization: Biological Roles and Uses in Hazard Identification" that was given at the annual Society of Toxicology meeting held March 6-9, 2006 in San Diego, California.

Identification of gene expression changes induced by chemical allergens in dendritic cells: opportunities for skin sensitization testing.

Cellular changes within resident skin dendritic cells (DCs) after allergen uptake and processing are critical events in the acquisition of skin sensitization. Here we describe the development of a set of selection criteria to derive a list of potential target genes from previous microarray analyses of human peripheral blood-derived (peripheral blood mononuclear cells (PBMCs)-DCs) treated with dinitrobenzene sulfonic acid for predicting skin-sensitizing chemicals. Based on those criteria, a probing evaluation of the target genes has been conducted using an extended chemical data set, comprising five skin irritants and 11 contact allergens.

Human dendritic cell activity against Histoplasma capsulatum is mediated via phagolysosomal fusion.

Histoplasma capsulatum is a fungal pathogen that requires the induction of cell-mediated immunity (CMI) for host survival. We have demonstrated that human dendritic cells (DC) phagocytose H. capsulatum yeasts and, unlike human macrophages (Mø) that are permissive for intracellular growth, DC killed and degraded the fungus.

Interactions of contact allergens with dendritic cells: opportunities and challenges for the development of novel approaches to hazard assessment.

The identification of potential skin sensitizing chemicals is a key step in the overall skin safety risk assessment process. Traditionally, predictive testing has been conducted in guinea pigs. More recently, the murine local lymph node assay (LLNA) has become the preferred test method for assessing skin sensitization potential.

Relationship of CD86 surface marker expression and cytotoxicity on dendritic cells exposed to chemical allergen.

Human peripheral blood-derived dendritic cells (DC) respond to a variety of chemical allergens by up-regulating expression of the co-stimulatory molecule CD86. It has been postulated that this measure might provide the basis for an in vitro alternative approach for the identification of skin sensitizing chemicals. We recently reported that DC, exposed in culture to the highest non-cytotoxic concentrations of various chemical allergens, displayed marginal up-regulation of membrane CD86 expression; the interpretation being that such changes were insufficiently sensitive for the purposes of hazard identification.

Interleukin-4- and interleukin-13-mediated host protection against intestinal nematode parasites.

Intestinal worm infections characteristically induce T-helper 2 cell (Th2) cytokine production. We reviewed studies performed with mice infected with either of two intestinal nematode parasites, Nippostrongylus brasiliensis or Trichinella spiralis, that evaluate the importance of the Th2 cytokine interleukin-4 (IL-4) and IL-13 in protection against these parasites. These studies demonstrate that while IL-4/IL-13 protect against both parasites by activating signal transducer and activator of transcription 6 (Stat6) through IL-4 receptor alpha (IL-4Ralpha) ligation, Stat6 activation protects against these parasites through different mechanisms.

Gene expression changes in peripheral blood-derived dendritic cells following exposure to a contact allergen.

A critical step in the induction of allergic contact allergy is the activation and subsequent migration of Langerhans cells (LC), an important antigen presenting dendritic cell (DC) of the skin. As the Langerhans cells migrate, they undergo a maturation process. It has been proposed that contact allergen exposure can induce DC maturation.

Overexpression of interleukin-4 in lungs of mice impairs elimination of Histoplasma capsulatum.

Protection against the pathogenic fungus Histoplasma capsulatum requires Th1 cytokines. Since interleukin-4 (IL-4) can inhibit both Th1 cytokine production and activity, we examined the effects of overproduction of IL-4 in the lung on the course of pulmonary histoplasmosis. IL-4 lung transgenic mice manifested a higher fungal burden in their lungs, but not spleens, compared to wild-type infected controls.

In vivo evidence for interferon-gamma-mediated homeostatic mechanisms in small intestine of the NHE3 Na+/H+ exchanger knockout model of congenital diarrhea.

Mice lacking NHE3, the major absorptive Na(+)/H(+) exchanger in the intestine, are the only animal model of congenital diarrhea. To identify molecular changes underlying compensatory mechanisms activated in chronic diarrheas, cDNA microarrays and Northern blot analyses were used to compare global mRNA expression patterns in small intestine of NHE3-deficient and wild-type mice. Among the genes identified were members of the RegIII family of growth factors, which may contribute to the increased absorptive area, and a large number of interferon-gamma-responsive genes.