Pseudomonas aeruginosaLipopolysaccharide Induction of Keratinocyte Proliferation, NF-κB, and Cyclin D1 Is Inhibited by Indomethacin

Abstract

NF-κB is activated during acute inflammatory states as well as in other injury response disease states. Several pathologic states in squamous tissue injury response are characterized by increased squamous proliferation. This study was performed to investigate the hypothesis that Pseudomonas aeruginosa LPS is able to activate a proliferative phenotype in squamous cells via NF-κB induction and that this NF-κB-mediated response may be abrogated with the classic anti-inflammatory agent indomethacin. EMSA, luciferase reporter gene experiments, Western blots, and cellular proliferation assays were performed in normal and transformed human keratinocytes after stimulation with P. aeruginosa LPS. EMSA and luciferase reporter gene assays showed a 3- to 5-fold induction of active NF-κB in human keratinocyte cell lines after stimulation with P. aeruginosa LPS. The stimulation correlated with significantly increased cellular proliferation. As one potential mechanism for this increase in proliferation, an NF-κB-specific activation of cyclin D1 was observed. Both the NF-κB induction and proliferation response were inhibited with indomethacin and in dominant negative stable transfection clones. P. aeruginosa LPS activates proliferation of human keratinocytes, potentially through the induction of NF-κB and cyclin D1. These findings suggest that bacterial components can contribute to proliferative disease states in squamous epithelium through NF-κB activation.

Expression of IL-23, VEGF and TLR2/TLR4 on Mononuclear Cells after Exposure to Pseudomonas Aeruginosa

“…This treatment determined a decrease in the proliferation obtained with CS; thus, the active component involved is at least in part correlated to the presence of lipase. The production of cytokines, angiogenesis, proliferation markers, cell cycle activators and apoptosis resistance are all factors that can contribute to abnormal cellular proliferation (4). We also showed that the CS increased IL-23 production from mononuclear cells in apparent absence of cytotoxicity.…”

“…bacterial infection and host inflammatory responses are intimately associated with the development of a full range of abnormal proliferative states in the host tissues that include even the development of cancer (4). The novel pathway of inflammation characterized by the production of Interleukin (IL)-I7 has been described in a variet y of immuneinflammatory diseases (5)(6) .…”

Toll-Like Receptors as Novel Therapeutic Targets for the Treatment of Pancreatic Cancer

“…Maspin is a member of the serpin family with well-established anti-metastatic activity in breast and prostate cancers. It was found that the metastatic behavior of isolated cells was dependent on the activation and nuclear accumulation of IKK (Preciado et al, 2005). Repression of Maspin transcription required nuclear translocation of catalytically active IKK , which occur only in advanced prostate tumors that contain inflammatory infiltrates and cells that express receptor activator of nuclear factor kappa-B ligand (RANKL) and LT : (Preciado et al, 2005).…”

“…It was found that the metastatic behavior of isolated cells was dependent on the activation and nuclear accumulation of IKK (Preciado et al, 2005). Repression of Maspin transcription required nuclear translocation of catalytically active IKK , which occur only in advanced prostate tumors that contain inflammatory infiltrates and cells that express receptor activator of nuclear factor kappa-B ligand (RANKL) and LT : (Preciado et al, 2005). RANKL can lead to repression of maspin-expression in an IKK -dependent manner (Zou et al, 1994;Luo et al, 2007).…”

“…The exact link between chronic inflammation and carcinogenesis is unclear, however many studies have shown that pro-inflammatory cytokines (TNF-, IL-6, IL-1, etc.) are important for the proliferation, survival, metastasis, and escape from immune surveillance of many of these cancers (Garcea et al, 2005;Lu et al, 2006), and have identified nuclear factor-ĸB (NF-ĸB) as a key modulator of inflammation-induced carcinogenesis (Chen et al, 1995;Guttridge et al, 1999;Hinz et al, 1999;Perkins, 2000;Coussens & Werb, 2002;Esposito et al, 2002;Ghosh & Karin, 2002;Karin & Lin, 2002;Li & Verma, 2002;O'Hanlon et al, 2002;Alexiou et al, 2003;Chen et al, 2003;Furbert-Harris et al, 2003;Lin & Karin, 2003;Greten et al, 2004;Huber et al, 2004;Luo et al, 2004;Niu et al, 2004;Pikarsky et al, 2004;Stoffel et al, 2004;Heyninck & Beyaert, 2005;Preciado et al, 2005;Yang et al, 2005a). Chronic inflammation as a result of disease, microbial infection, and/or obesity is an important risk factor for the development of a variety of cancers Kuper et al, 2000;Calle & Kaaks, 2004;Khatami, 2011) (Table 2).…”