JNK1 and JNK2 differently regulate IL-12 production in THP-1 macrophage cells
Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan.Cytokine (Impact Factor: 2.66). 08/2010; 51(2):127-31. DOI: 10.1016/j.cyto.2010.04.002
Macrophages play a key role in initiating the innate responses to infection by secreting cytokines such as interleukin-12 (IL-12). This study defined the distinct regulation of lipopolysaccharide (LPS)-mediated IL-12 production by c-jun NH(2)-terminal kinase (JNK)1 and JNK2 isoforms in human macrophages. Knockdown of JNK1 and JNK2 by small interference RNA (siRNA) reduced and enhanced LPS-induced IL-12 p40 production in THP-1 macrophage cells, respectively. The simultaneous knockdown of JNK1 and JNK2 augmented LPS-induced IL-12 production as well as a specific JNK inhibitor. In addition, transfection of siRNA against phosphoinositide 3-kinase (PI3K) p110beta attenuated LPS-induced IL-12 production and JNK1 phosphorylation, while not affecting JNK2 phosphorylation. These findings indicate that JNK1- and JNK2-mediated signaling plays a positive and a negative role, respectively, in LPS-induced IL-12 production and PI3K p110beta controls LPS-induced JNK1 activation, not JNK2 activation, resulting in the positive regulation of IL-12 production in THP-1 macrophage cells.
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ABSTRACT: The Ganoderma lucidum (G. lucidum) is one of the oriental fungi that has been reported to have immunomodulatory properties. Although effect of β-glucans from G. lucidum has been well documented, little is known about how other major bioactive components, the triterpenes, contribute to the immunomodulatory function of G. lucidum. Here, we showed that triterpenes-rich extract of antlered form of G. lucidum (G. lucidum AF) induces TNFα production in monocytic THP-1 cells. Furthermore, the extract also synergized with lipopolysaccharide (LPS) to induce TNFα production in THP-1 cells, suggesting an immunostimulatory role of triterpenes-rich extract of G. lucidum AF. Notably, the extract enhanced LPS-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK), while it suppressed LPS-induced phosphorylation of c-Jun N-terminal kinase (JNK) MAPK. p38 Inhibitor suppressed TNFα production, while JNK inhibitor enhanced TNFα production, implying that synergistic effect of the extract may work by modulating p38 and JNK MAPKs. Moreover, we found that the triterpenes-rich extract of G. lucidum AF contains high amounts of lucidenic acids. Lucidenic acid-A, -F and -D(2), which seem to dominantly exist in the extract, were purified from the triterpenes-rich extract. We also identified Lucidenic acid-A and -F as modulators of JNK and p38, respectively. Thus, our data demonstrate that lucidenic acids-rich extract from G. lucidum AF enhances LPS-induced immune responses in monocytic THP-1 cells possibly via the modulation of p38 and JNK MAPKs activation.
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ABSTRACT: Granulocytopenia frequently occurs in alcohol abusers with severe bacterial infection, which strongly correlates with poor clinical outcome. Knowledge of the molecular mechanisms underlying the granulopoietic response to bacterial infection remains limited. This study investigated the involvement of stem cell antigen-1 expression by granulocyte lineage-committed progenitors in the granulopoietic response to septicemia and how alcohol affected this response. : Laboratory investigation. University laboratory. Male Balb/c mice. Thirty mins after intraperitoneal injection of alcohol (20% ethanol in saline at 5 g of ethanol/kg) or saline, mice received an intravenous Escherichia coli challenge. E. coli septicemia activated stem cell antigen-1 expression by marrow immature granulocyte differentiation antigen-1 precursors which correlated with an increase in proliferation, granulocyte macrophage colony-forming unit production, and expansion of this granulopoietic precursor cell pool. Acute alcohol treatment suppressed stem cell antigen-1 activation and inhibited the infection-induced increases in proliferation, granulocyte macrophage colony-forming unit production, and expansion the of immature granulocyte differentiation antigen-1 precursor cell population. Consequently, recovery of the marrow mature granulocyte differentiation antigen-1 cell population after E. coli challenge was impaired. Stem cell antigen-1 was induced in sorted granulocyte differentiation antigen-1, stem cell antigen-1' cells by lipopolysaccharide-stimulated C-Jun kinase activation that was also inhibited by alcohol. Furthermore, stem cell antigen-1 knockout mice failed to expand the marrow immature granulocyte differentiation antigen-1 cell pool and demonstrated fewer newly produced granulocytes in the circulation after the E. coli challenge. Alcohol suppresses the stem cell antigen-1 response in granulocyte lineage-committed precursors and restricts granulocyte production during septicemia, which may serve as a novel mechanism underlying impaired host defense in alcohol abusers.
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ABSTRACT: Laparoscopic sleeve gastrectomy is commonly performed using multiple ports. The quest to minimize surgical trauma has led to the development of single port laparoscopy, which has been shown to be a safe, less-invasive method of performing a variety of abdominal surgeries. We describe the feasibility and safety of single port sleeve gastrectomy (SPSG) for morbid obesity at an academic affiliate of a university hospital. A total of 25 patients undergoing elective SPSG were compared with a demographically similar contemporaneous cohort of 9 patients who underwent standard multiple port laparoscopic sleeve gastrectomy. The data collected included the operative time, narcotic consumption, duration of patient controlled analgesia use, subjective pain scores, and length of stay. The patients undergoing SPSG experienced significantly less pain at 1 hour postoperatively (P = .039). No statistically significant difference was found in pain between the 2 groups at 12 and 24 hours (P = .519 and P = .403, respectively). The quantity of narcotic use (P = .538), duration of patient controlled analgesia use (P = .820), and length of stay (P = .571) were not significantly different between the 2 groups. The operative time for SPSG was 118 minutes versus 101 minutes for multiple port surgery (P = .160). SPSG is safe and feasible for selected patients. The patients undergoing SPSG reported significantly less pain at the first postoperative hour. No significant differences between the 2 groups were seen in any of the other postoperative parameters.
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