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Hyperglycemia is a result of impaired insulin action on glucose production and disposal, and a major target of antidiabetic therapies. The study of insulin-independent regulatory mechanisms of glucose metabolism may identify new strategies to lower blood sugar levels. Here we demonstrate an unexpected metabolic function for IL-13 in the control of hepatic glucose production. IL-13 is a Th2 cytokine known to mediate macrophage alternative activation. Genetic ablation of Il-13 in mice (Il-13-/-) resulted in hyperglycemia, which progressed to hepatic insulin resistance and systemic metabolic dysfunction. In Il-13-/- mice, upregulation of enzymes involved in hepatic gluconeogenesis was a primary event leading to dysregulated glucose metabolism. IL-13 inhibited transcription of gluconeogenic genes by acting directly on hepatocytes through Stat3, a noncanonical downstream effector. Consequently, the ability of IL-13 to suppress glucose production was abolished in liver cells lacking Stat3 or IL-13 receptor α1 (Il-13rα1), which suggests that the IL-13Rα1/Stat3 axis directs IL-13 signaling toward metabolic responses. These findings extend the implication of a Th1/Th2 paradigm in metabolic homeostasis beyond inflammation to direct control of glucose metabolism and suggest that the IL-13/Stat3 pathway may serve as a therapeutic target for glycemic control in insulin resistance and type 2 diabetes.

The TNF-family cytokine TL1A costimulates T cells through its receptor DR3 and is required for diverse autoimmune disease models, but its role in innate lymphocyte biology has not been explored. Transgenic mice chronically expressing TL1A have increased activated T cells and develop small intestinal pathology characterized by high levels of IL-13, muscular and goblet cell hyperplasia, and infiltration with immune cells, all of which depend on DR3. Genetically eliminating T cells reduces T cell hyperactivation and gut infiltration with lymphocytes but not IL-13 production or mucosal hyperplasia. These data suggest that TL1A can induce another cell type to produce IL-13 and induce gastrointestinal pathology. Using a DsRED reporter mouse for IL-13, we find that the major IL-13 producing cells in TL1A transgenic mice lack T and B cell lineage markers and are phenotypically similar to ’type 2’ innate lymphocytes (ILC2) which expand and produce IL-13 in response to IL-25, IL-33 or parasitic infection. TL1A directly promotes IL-13 production by ILC2 ex-vivo. However, DR3 deficient mice mount a vigorous response to the intestinal nematode Nippostrongylus brasiliensis, and IL-13 producing innate lymphocytes can be expanded by IL-25 in the absence of DR3. Thus, TL1A can directly induce IL-13 production by innate lymphocytes through mechanisms distinct from parasitic infection. TL1A may be an attractive target for immunotherapy of diverse diseases associated with this cytokine.

Disease conditions associated with pulmonary fibrosis are progressive and have a poor long-term prognosis with irreversible changes in airway architecture leading to marked morbidity and mortalities. Currently there are limited effective therapeutics for pulmonary fibrosis due to an inadequate understanding of the pathogenic process and underlying mechanisms. We now show that in human idiopathic pulmonary fibrosis (IPF) the cytokine interleukin (IL)-25 positively correlates with periostin a marker human pulmonary fibrosis, and the presence of IL-13-producing type 2 innate lymphoid cells (ILC2) in the lung. Using murine models of pulmonary fibrosis we demonstrate an essential role for IL-25-elicited ILC2 in the generation of pulmonary collagen deposition, independent of an adaptive T cell response. Furthermore, we define a mechanism whereby IL-25 evokes ILC2 to induce pulmonary fibrosis via the alternative activation of macrophages in the lung. Collectively, we present a new innate mechanism for the generation of pulmonary fibrosis, via IL-25 and ILC2 that occurs independently of T cell-mediated antigen-specific immune responses. These results indicate that IL-25 and ILC2 are potential therapeutic targets for the treatment of human fibrotic diseases where antigen-independent damage responses may magnify the disease.

Patient satisfaction with the interpersonal and amenities aspects of care in a psychiatric hospital was investigated in an Australian setting. The study was carried out among the long-term residential population of a psychiatric hospital and involved 112 out of 195, or 57% of all eligible patients. Cluster analysis identified seven major groups of related items concerning the patients' views of hospital life and their perception of problems. The study largely replicated the findings of an English investigation, showing that many of the same underlying clusters of satisfaction-dissatisfaction with life in a psychiatric hospital emerge, across widely geographically separated settings. The results from the present study further indicate that improvements in autonomy for the patients and a greater say in the running of wards are more important factors contributing to satisfaction with life in a hospital than the physical surroundings themselves.