Dong-Gu Jeong

IL-10 suppresses bactericidal response of macrophages against Salmonella Typhimurium.

We report, herein, an attempt to determine whether an IL-10-induced immunological state affects the response of macrophages against Salmonella Typhimurium (ST). Pretreatment with mrIL-10 induced the intracellular invasion of ST into macrophages in a dose-dependent manner. It also activated AKT phosphorylation, cyclin D1, Bcl-XL, and COX-2 upon ST infection, which may correlate with Salmonella’s survival within the macrophages. However, I-κB phosphorylation was shown to be inhibited, along with the expression of TNF-α and MIP-2α mRNA. Therefore, IL-10 not only suppresses the bactericidal response of macrophages against ST, but also ultimately causes infected macrophages to function as hosts for ST replication.

Difference in Resistance to Streptococcus pneumoniae Infection in Mice

Streptococcus pneumoniae is a major pathogen that causes various diseases, including pneumonia and sepsis, as millions of people suffer from S. pneumoniae infection worldwide. To better understand the immune and inflammatory responses to S. pneumoniae, we produced murine models. To investigate the differences between intranasal and intratracheal infection, BALB/c mice were infected with S. pneumoniae D39 intranasally or intratracheally. Mice showed no significant differences in survival rates, body weight changes, and bacterial loads. To investigate resistance and susceptibility among mouse strains, BALB/c, C57BL/6J, tumor necrosis factor-α (TNF-α) knockout, and interleukin-10 (IL-10) knockout mice were infected with S. pneumoniae D39 via intranasal or intravenous routes. In this study, BALB/c and C57BL/6J mice were resistant, IL-10 knockout mice were intermediate, and TNF-α knokout mice were susceptible to S. pneumoniae infection. These data show that intranasal and intratracheal infection induced similar results after S. pneumoniae infection, and the genetic background of mice must be considered when studying S. pneumoniae infection in vivo.

Lentivirus-mediated shRNA targeting of cyclin D1 enhances the chemosensitivity of human gastric cancer to 5-fluorouracil

Gastric cancer is one of the major public health problems. Despite new chemotherapeutic treatments, the prognosis of gastric cancer remains poor. 5-Fluorouracil (5-FU) is used as a standard chemotherapy drug in gastric cancer. However, 5-FU resistance develops frequently and is a main cause of chemotherapy failure in human gastric cancer. Overexpression of cyclin D1 is related to rapid cell growth, a poor prognosis and increased chemoresistance in several types of cancers. In this study, we investigated whether treatment of gastric cancer cells with shRNA targeting cyclin D1 (ShCCND1) or 5-FU, alone or in combination, influences the activation of phosphorylated AKT (pAKT) and pNFκB, which are markers that are increased in 5-FU chemoresistance. We also investigated the effect of combined treatment with ShCCND1 and 5-FU on cell growth and chemosensitivity to 5-FU in the gastric cancer cell line AGS. The data showed that ShCCND1-mediated cyclin D1 downregulation in AGS cells significantly inhibited cell proliferation, cell mobility and clonogenicity. In addition, combined treatment with ShCCND1 and 5-FU significantly decreased the survival rate of AGS cells, compared to single-treatment with either agent. These results demonstrated that ShCCND1 increases 5-FU chemosensitivity, a conclusion that is also supported by the concomitant reduction in expression of pAKT and pNFκB, increase of G1 arrest and induction of apoptosis. Taken together, these data provide further evidence that therapeutic strategies targeting cyclin D1 may have the dual advantage of suppressing the growth of cancer cells, while enhancing their chemosensitivity.

Tumor necrosis factor-alpha deficiency impairs host defense against Streptococcus pneumoniae.

Streptococcus pneumoniae is a major human pathogen that is involved in community-acquired pneumonia. Tumor necrosis factor-alpha (TNF-α) is a pro-inflammatory cytokine that activates immune responses against infection, invasion, injury, or inflammation. To study the role of TNF-α during S. pneumoniae infection, a murine pneumococcal pneumonia model was used. We intranasally infected C57BL/6J wild-type (WT) and TNF-α knockout (KO) mice with S. pneumoniae D39 serotype 2. In TNF-α KO mice, continuous and distinct loss of body weight, and low survival rates were observed. Bacterial counts in the lungs and blood of TNF-α KO mice were significantly higher than those in WT mice. Histopathological lesions in the spleen of TNF-α KO mice were more severe than those in WT mice. In TNF-α KO mice, severe depletion of white pulp was observed and the number of apoptotic cells was significantly increased. Interferon-gamma (IFN-γ), IL-12p70 and IL-10 levels in serum were significantly increased in TNF-α KO mice. TNF-α is clearly involved in the regulation of S. pneumoniae infections. Early death and low survival rates of TNF-α KO mice were likely caused by a combination of impaired bacterial clearance and damage to the spleen. Our findings suggest that TNF-α plays a critical role in protecting the host from systemic S. pneumoniae infection.