Regulatory T cells (Tregs) play a critical role in the maintenance of immunological self-tolerance. Naïve human or murine T cell treatment with the inhibitory cytokine IL-35 induces a regulatory population, termed iTR35, that mediates suppression via IL-35, but not IL-10 or TGFβ, neither express nor require Foxp3, are strongly suppressive in five in vivo models, and exhibit in vivo stability. Treg-mediated suppression induces iTR35 generation in an IL-35- and IL-10-dependent manner in vitro, and in inflammatory conditions in vivo in Trichuris-infected intestines and within the tumor microenvironment, where they appear to contribute to the regulatory milieu. iTR35 may constitute a key mediator of infectious tolerance, may contribute to Treg-mediated tumor progression, and ex vivo generated iTR35 may possess therapeutic utility.

Human umbilical vein endothelial cells have recently been shown to respond to C5a with increases in intracellular Ca2", production of D-myo-inositol 1,4,5-triphosphate and superoxide anion generation. In the current studies, C5a has been found to cause in a time-and dose-dependent manner rapid expression of endothelial P-selectin, secretion of von Willebrand factor, and adhesiveness for human neutrophils. The effects of C5a in P-selectin expression and adhesiveness of neutrophils were similar to the effects of histamine and thrombin on endothelial cells. The adhesiveness of C5a-stimulated endothelium for neutrophils was blocked by anti-P-selectin, but not by antibodies to intercellular adhesion molecule 1, E-selectin, or CD18. A cell-based ELISA technique has confirmed upregulation of P-selectin in endothelial cells exposed to C5a. Binding of C5a to endothelial cells has been demonstrated, with molecules bound being -10% of those binding to neutrophils. By a reverse transcriptase-PCR technique, endothelial cells have been shown to contain mRNA for the C5a receptor. These data suggest that C5a may be an important inflammatory mediator for the early adhesive interactions between neutrophils and endothelial cells in the acute inflammatory response. (J. Clin.

During inflammation, neutrophils migrate from the vascular lumen into extravascular sites. In vitro assays have suggested that platelet-endothelial cell adhesion molecule-1 [PECAM-1 (CD31)], a member of the immunoglobulin superfamily, is required for the transmigration of neutrophils across endothelial monolayers. Antibody to human PECAM-1, which cross-reacts with rat PECAM-1, was found to block not only in vivo accumulation of rat neutrophils into the peritoneal cavity and the alveolar compartment of the lung but also neutrophil accumulation in human skin grafts transplanted onto immunodeficient mice. On the basis of these findings in three different models of inflammation, it appears that PECAM-1 is required for neutrophil transmigration in vivo and may thus be a potential therapeutic target.

Life history characteristics of 54 Ontario lake trout (Salvelinus namaycush) populations vary with differences in lake area (range 25-450 000 ha) and total dissolved solids (TDS) (range 15-180 mg·L-1). Populations from large lakes exhibit greater maximum sizes, greater ages and sizes at first maturity, lower natural mortality rates, and lower sustainable yields. Populations from high-TDS lakes exhibit higher growth rates in early life, lower ages at first maturity, larger sizes at first maturity, and higher natural mortality rates. Angler catchability increases significantly at low population densities. With these relationships included in an age-structured population model, we found that the fishing mortality rate at maximum equilibrium yield ranges from 0.12·year-1 for a 100-ha, low-TDS lake to 0.37·year-1 for a 10 000-ha, high-TDS lake; the fishing effort level at maximum equilibrium yield ranges from 6.6 angler-h·ha-1· year-1 for a 100-ha, low-TDS lake to 4.0 angler-h·ha-1·year-1 for a 10 000-ha, high-TDS lake. Populations from small, low-TDS lakes are more sensitive to overexploitation than populations from large, high-TDS lakes. Easily measured, environmental correlates of life history characters may be common among fish species and are useful in developing exploitation guidelines for populations that are not well studied.

The heterodimeric cytokine interleukin 27 (IL-27) signals through the IL-27Rα subunit combined with gp130, a common receptor chain utilized by several cytokines, including IL-6. Interestingly, the IL-27 subunits p28 and EBI3 are not always co-expressed, suggesting that they may have unique functions. Here, we show IL-27p28, independent of EBI3 antagonized cytokine signaling through gp130 and IL-6 mediated production of IL-17 and IL-10. Similarly, the ability to generate antibody responses was dependent on the activity of gp130-signaling cytokines. IL-27p28 transgenic mice showed a major defect in germinal center formation and antibody production. Thus, IL-27p28, as a natural antagonist of gp130-mediated signaling, may be useful as a therapeutic for managing inflammation mediated by cytokines that signal through gp130.