Interleukin 6 (IL-6) is involved in innate and adaptive immune responses to defend against pathogens. It also participates in the process of influenza infection by affecting viral clearance and immune cell responses. However, whether IL-6 impacts lung repair in influenza pathogenesis remains unclear. Here, we studied the role of IL-6 in acute influenza infection in mice. IL-6-deficient mice infected with influenza virus exhibited higher lethality, lost more body weight and had higher fibroblast accumulation and lower extracellular matrix (ECM) turnover in the lung than their wild-type counterparts. Deficiency in IL-6 enhanced proliferation, migration and survival of lung fibroblasts, as well as increased virus-induced apoptosis of lung epithelial cells. IL-6-deficient lung fibroblasts produced elevated levels of TGF-β, which may contribute to their survival. Furthermore, macrophage recruitment to the lung and phagocytic activities of macrophages during influenza infection were reduced in IL-6-deficient mice. Collectively, our results indicate that IL-6 is crucial for lung repair after influenza-induced lung injury through reducing fibroblast accumulation, promoting epithelial cell survival, increasing macrophage recruitment to the lung and enhancing phagocytosis of viruses by macrophages. This study suggests that IL-6 may be exploited for lung repair during influenza infection.

Cathepsins have long been considered as housekeeping molecules. However, specific functions have also been attributed to each one of these lysosomal proteases. Squamous cell carcinoma antigen (SCCA...

Cancer and embryonic stem cells exhibit similar behavior, including immortal, undifferentiated, and invasive activities. Here, we show that in clinical samples bladder tumors with intense expression of stem cell marker Oct-3/4 (also known as POU5F1) are associated with further disease progression, greater metastasis, and shorter cancer-related survival compared with those with moderate and low expressions. Expression of Oct-3/4 is detected in human bladder transitional cell carcinoma samples and cell lines. Overexpression of Oct-3/4 enhances, whereas knockdown of Oct-3/4 expression by RNA interference reduces, migration and invasion of bladder cancer cells. Oct-3/4 can up-regulate fibroblast growth factor-4 and matrix metalloproteinase-2 (MMP-2), MMP-9, and MMP-13 production, which may contribute to tumor metastasis. Finally, we show that Ad5WS4, an E1B-55 kD–deleted adenovirus driven by the Oct-3/4 promoter, exerts potent antitumor activity against bladder cancer in a syngeneic murine tumor model. Therefore, our results implicate that Oct-3/4 may be useful as a novel tumor biological and prognostic marker and probably as a potential therapeutic target for bladder cancer. [Cancer Res 2008;68(15):6281–91]

Objective: MicroRNA (miRNA) plays a role in autoimmune diseases. MiRNA‐223 (miR‐223) is up‐regulated in patients with rheumatoid arthritis (RA) and is involved in osteoclastogenesis, which contributes to erosive disease. The aim of this study was to test the feasibility of using lentiviral vectors expressing the miR‐223 target sequence (miR‐223T) to suppress miR‐223 activity as a therapeutic strategy in a mouse model of collagen‐induced arthritis (CIA).Methods: Levels of miR‐223 in the synovial tissue of patients with RA or osteoarthritis (OA), as well as in the ankle joints of mice with CIA, were determined by quantitative reverse transcriptase–polymerase chain reaction (RT‐PCR). Lentiviral vectors expressing miR‐223T (LVmiR‐223T) or luciferase short hairpin RNA (LVshLuc) as a control vector were injected intraperitoneally into mice with CIA. Treatment responses and disease‐related bone mineral density were monitored. Levels of nuclear factor 1A (NF‐1A), a direct target of miR‐223, and macrophage colony‐stimulating factor receptor (M‐CSFR), which is critical for osteoclastogenesis, were measured by immunohistochemistry and quantitative RT‐PCR. Osteoclasts were assessed by tartrate‐resistant acid phosphatase staining.Results: MiR‐223 expression was significantly higher in the synovium of RA patients and in the ankle joints of mice with CIA as compared to OA patients and normal mice. LVmiR‐223T treatment reduced the arthritis score, histologic score, miR‐223 expression, osteoclastogenesis, and bone erosion in mice with CIA. Down‐regulation of miR‐223 with concomitant increases in NF‐1A levels and decreases in M‐CSFR levels was detected in the synovium of LVmiR‐223T–treated mice.Conclusion: This study is the first to demonstrate that lentivirus‐mediated silencing of miR‐223 can reduce disease severity of experimental arthritis. Furthermore, our results indicate that inhibition of miR‐223 activity should be further explored as a therapeutic strategy in RA.

Innate immune response is important for viral clearance during influenza virus infection. Galectin-1, which belongs to S-type lectins, contains a conserved carbohydrate recognition domain that recognizes galactose-containing oligosaccharides. Since the envelope proteins of influenza virus are highly glycosylated, we studied the role of galectin-1 in influenza virus infection in vitro and in mice. We found that galectin-1 was upregulated in the lungs of mice during influenza virus infection. There was a positive correlation between galectin-1 levels and viral loads during the acute phase of viral infection. Cells treated with recombinant human galectin-1 generated lower viral yields after influenza virus infection. Galectin-1 could directly bind to the envelope glycoproteins of influenza A/WSN/33 virus and inhibit its hemagglutination activity and infectivity. It also bound to different subtypes of influenza A virus with micromolar dissociation constant ( K _d ) values and protected cells against influenza virus-induced cell death. We used nanoparticle, surface plasmon resonance analysis and transmission electron microscopy to further demonstrate the direct binding of galectin-1 to influenza virus. More importantly, we show for the first time that intranasal treatment of galectin-1 could enhance survival of mice against lethal challenge with influenza virus by reducing viral load, inflammation, and apoptosis in the lung. Furthermore, galectin-1 knockout mice were more susceptible to influenza virus infection than wild-type mice. Collectively, our results indicate that galectin-1 has anti-influenza virus activity by binding to viral surface and inhibiting its infectivity. Thus, galectin-1 may be further explored as a novel therapeutic agent for influenza.