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Background: TH2 inflammation and bronchial smooth muscle cell (BSMC) hyperplasia are characteristic features of asthma, but whether these phenomena are linked remains unknown. This study aims to define the effect of the TH2 cytokines IL-4 and IL-13 on human BSMC proliferation when administered alone or in combination with the fibroblast growth factor 2 (FGF2) growth factor. In addition, the effects of the proinflammatory mediators TNFα and IL-1β and the involvement of members of the well-known family of platelet-derived growth factor (PDGF) mitogens were tested. Methods: BSMC proliferation was measured by crystal violet staining and PDGF and PDGF receptor (PDGFR) expression were determined by RT-PCR, immunocytochemistry, ELISA, flow cytometry and dot plot analysis. Results: Neither IL-4 nor IL-13 alone induced BSMC proliferation, despite both being potent inducers of PDGF-CC. However, following a pretreatment with FGF2, which increased PDGFR α chain expression, both IL-4 and IL-13 increased FGF2-induced BSMC proliferation in a time- and concentration-dependent manner. TNFα and IL-1β did not affect basal or FGF2-induced BSMC proliferation, but both proinflammatory mediators enhanced the proliferative synergism between FGF2 and the TH2 cytokines. Conclusions: IL-4 and IL-13 potently induce FGF2-primed BSMC proliferation via an autocrine loop involving PDGFRα and PDGF-CC, and this proliferative synergism is amplified by proinflammatory cytokines.

This investigation focused on studying the effects of insulin-dependent diabetes mellitus and insulin treatment on absorption of glycylsarcosine (Gly-Sar) across the Sprague-Dawley rat jejunum, using in situ perfusion in a physiologic acidic microenvironment at pH 6.0. Rats were divided into five groups: normal controls in group I, normal colchicine-treated rats in group II, normal cytochalasin-treated rats in group III, streptozotocin-induced diabetic rats in group IV, and insulin-treated diabetic rats in group V. Histologic studies of the five different groups showed morphologic changes upon induction of diabetes and treatments with colchicine and cytochalasin and several variations in post-1 month diabetic rats treated with insulin. The rate of uptake of Gly-Sar was significantly reduced in the diabetic state. The comparison of colchicine-treated and cytochalasin-treated rats to the diabetic group suggests that an intact cytoskeleton and tight junctions may play a role in jejunal dipeptide absorption. In the diabetic and insulin-treated group, the dipeptide influx rate was significantly increased compared to that of the nontreated controls. The regulation of the PepT 1 symporter was further assessed by immunostaining and Western blot analyses in the normal, diabetic, and diabetic and insulin-treated groups. Our results showed that a downregulation of PepT 1 in the diabetics seemed to be due in part to the low systemic insulin levels, and not necessarily to hyperglycemia. In addition, the results suggest a probable role of systemic insulin binding at the vascular site of the jejunal epithelium, and the role that this hormone may be playing in the regulation and probably cellular trafficking of PepT1.

To identify new regulators of innate antiviral immunity, we completed the first genome-wide gene silencing screen assessing the transcriptional response at the interferon-β gene (IFNB1) promoter following Sendai virus (SeV) infection. We identified 237 potential modulator genes for which negative or positive actions of gene products were mapped to the different steps of the antiviral responses from virus sensing, signal propagation/amplification up to the feedback regulation. In the present study, we will report on specific proteins that promote IFNB1 expression and innate antiviral response. The functional genomics screen uncovers a novel link between WNT family members and innate antiviral immunity. We show that virus-induced secretion of WNT2B and WNT9B down regulates IFNB1 and ISG56 expression in a β-catenin (CTNNB1)-dependent mechanism. The antiviral response is drastically reduced by GSK3 inhibitors but completely restored in CTNNB1 knockdown cells. The findings confirm a novel regulation of the innate antiviral response by a canonical WNT/GSK3/CTNNB1 pathway in a negative feedback mechanism. The study identifies novel avenues for therapeutically regulating innate immunity for effective treatment of viral infection and prevention of excessive response in autoimmune diseases.