VEN-120, a Recombinant Human Lactoferrin, Promotes a Regulatory T Cell [Treg] Phenotype and Drives Resolution of Inflammation in Distinct Murine Models of Inflammatory Bowel Disease.

Background And Aims: Inflammatory bowel disease [IBD] is characterised by a disruption of immune homeostasis, which is tightly regulated to protect against harmful pathogens yet not react to commensal antigens. Animal studies indicate that regulatory T cells [Treg] modulate the immune response to prevent IBD development. Lactoferrin [LF] is an endogenous anti-inflammatory pleiotropic protein secreted at high concentrations in colostrum and at mucosal sites.

IFN-γ-mediated induction of an apical IL-10 receptor on polarized intestinal epithelia.

Cytokines secreted at sites of inflammation impact the onset, progression, and resolution of inflammation. In this article, we investigated potential proresolving mechanisms of IFN-γ in models of inflammatory bowel disease. Guided by initial microarray analysis, in vitro studies revealed that IFN-γ selectively induced the expression of IL-10R1 on intestinal epithelia.

HIF-dependent regulation of AKAP12 (gravin) in the control of human vascular endothelial function.

Hypoxia has been widely implicated in many pathological conditions, including those associated with inflammation and tumorigenesis. A number of recent studies have implicated hypoxia in the control of vasculogenesis and permeability, the basis for which is not fully understood. Here we examine the transcriptional regulation of angiogenesis and permeability by hypoxia in endothelial cells.

An endogenously anti-inflammatory role for methylation in mucosal inflammation identified through metabolite profiling.

Tissues of the mucosa are lined by an epithelium that provides barrier and transport functions. It is now appreciated that inflammatory responses in inflammatory bowel diseases are accompanied by striking shifts in tissue metabolism. In this paper, we examined global metabolic consequences of mucosal inflammation using both in vitro and in vivo models of disease.

Anti-inflammatory actions of adrenomedullin through fine tuning of HIF stabilization.

In intact mucosal tissues, epithelial cells are anatomically positioned in proximity to a number of subepithelial cell types, including endothelia. A number of recent studies have suggested that imbalances between energy supply and demand can result in "inflammatory hypoxia." Given these associations, we hypothesized that endothelial-derived, hypoxia-inducible mediators might influence epithelial function.

IFN-γ attenuates hypoxia-inducible factor (HIF) activity in intestinal epithelial cells through transcriptional repression of HIF-1β.

Numerous studies have revealed that hypoxia and inflammation occur coincidentally in mucosal disorders, such as inflammatory bowel disease. During inflammation, epithelial-expressed hypoxia-inducible factor (HIF) serves an endogenously protective function. In this study, we sought to explore how mucosal immune responses influence HIF-dependent end points.

Resolvin E1-induced intestinal alkaline phosphatase promotes resolution of inflammation through LPS detoxification.

Resolvin-E1 (RvE1) has been demonstrated to promote inflammatory resolution in numerous disease models. Given the importance of epithelial cells to coordination of mucosal inflammation, we hypothesized that RvE1 elicits an epithelial resolution signature. Initial studies revealed that the RvE1-receptor (ChemR23) is expressed on intestinal epithelial cells (IECs) and that microarray profiling of cells exposed to RvE1 revealed regulation of inflammatory response gene expression.

Signaling through the A2B adenosine receptor dampens endotoxin-induced acute lung injury.

Sepsis and septic acute lung injury are among the leading causes for morbidity and mortality of critical illness. Extracellular adenosine is a signaling molecule implicated in the cellular adaptation to hypoxia, ischemia, or inflammation. Therefore, we pursued the role of the A2B adenosine receptor (AR) as potential therapeutic target in endotoxin-induced acute lung injury.

Hypoxia-inducible factor-dependent regulation of platelet-activating factor receptor as a route for gram-positive bacterial translocation across epithelia.

Mucosal surfaces, such as the lung and intestine, are lined by a monolayer of epithelia that provides tissue barrier and transport function. It is recently appreciated that a common feature of inflammatory processes within the mucosa is hypoxia (so-called inflammatory hypoxia). Given the strong association between bacterial translocation and mucosal inflammatory disease, we hypothesized that intestinal epithelial hypoxia influences bacterial translocation.

Contribution of adenosine A2B receptors to inflammatory parameters of experimental colitis.

Inflammatory diseases influence tissue metabolism, significantly altering the profile of extracellular adenine nucleotides. A number of studies have suggested that adenosine (Ado) may function as an endogenously generated anti-inflammatory molecule. Given the central role of intestinal epithelial cells to the development of colitis, we hypothesized that specific Ado receptors would contribute to disease resolution in mucosal inflammation as modeled by dextran sodium sulfate (DSS) colitis.

Selective induction of integrin beta1 by hypoxia-inducible factor: implications for wound healing.

Because of localized vascular damage and increased tissue oxygen demand, wound healing occurs in a relatively hypoxic microenvironment. These features are particularly relevant to wound healing and fibrosis in chronic inflammatory conditions, such as Crohn's disease and ulcerative colitis. In these studies, we sought to identify the contribution of hypoxia to mechanisms of wound repair in a model of the intestinal submucosa.

Neutrophils as sources of extracellular nucleotides: functional consequences at the vascular interface.

Nucleotide signaling is currently an area of intense investigation. Extracellular adenosine triphosphate (ATP) liberated during hypoxia or inflammation can either signal directly to purinergic receptors or, after phosphohydrolytic metabolism, can activate surface adenosine receptors. Given the association of polymorphonuclear leukocytes (PMNs) with adenine nucleotide/nucleoside signaling in the inflammatory milieu, it was recently demonstrated that PMNs actively release ATP via a connexin 43 hemichannel-dependent mechanism.

Control of IFN-alphaA by CD73: implications for mucosal inflammation.

Inflammatory diseases influence tissue metabolism, altering regulation of extracellular adenine nucleotides, with a resultant protective influence of adenosine. Ecto-5'-nucleotidase (CD73) is a central surface enzyme generating extracellular adenosine. Thus, we hypothesized that CD73 is protective in mucosal inflammation as modeled by trinitrobenzene sulfonate (TNBS) colitis.

Interleukin-8 signaling promotes translational regulation of cyclin D in androgen-independent prostate cancer cells.

We have shown previously that interleukin-8 (IL-8) and IL-8 receptor expression is elevated in tumor cells of human prostate biopsy tissue and correlates with increased cyclin D1 expression. Using PC3 and DU145 cell lines, we sought to determine whether IL-8 signaling regulated cyclin D1 expression in androgen-independent prostate cancer (AIPC) cells and to characterize the signaling pathways underpinning this response and that of IL-8-promoted proliferation. Administration of recombinant human IL-8 induced a rapid, time-dependent increase in cyclin D1 expression in AIPC cells, a response attenuated by the translation inhibitor cycloheximide but not by the RNA synthesis inhibitor, actinomycin D.

A Rho-dependent actin purse-string is involved in wound repair in the early chick amnion following surgical puncture.

This study examined the mechanism of wound repair in the early chick amnion following surgical puncture. The chick amnion is a bilayered membrane with ultrastructural features similar to the human amnion, and thus may provide a model of the consequences of amnion puncture following first trimester amniocentesis in humans. Chick amnion was wounded on day 4-5 of incubation.