Inhibition of LPS-induced cyclooxygenase 2 and nitric oxide production by transduced PEP-1-PTEN fusion protein in Raw 264.7 macrophage cells

Lee, Sun Hwa; Lee, Yeom Pyo; Kim, So Young; Jeong, Min Seop; Lee, Min Jung; Kang, Hye Won; Jeong, Hyung Jae; Kim, Dae Won; Sohn, Eun Joung; Jang, Sang Ho; Kim, Yeon Hyang; Kwon, Hee Jung; Cho, Sung Woo; Park, Jinseu; Eum, Won Sik; Choi, Soo Young

doi:10.3858/emm.2008.40.6.629

Cited by 9 publications

(6 citation statements)

References 52 publications

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“…Our results in the present study further showed that LPS-induced cell proliferation, differentiation and collagen secretion could be inhibited in lung fibroblasts transfected with a PTEN overexpression lentivirus, which increased both PTEN levels and its dephosphorylation activity. Similar results using a PEP-1-PTEN fusion protein transfected into macrophages [ 35 ] or adenovirus-mediated PTEN gene transferred into synovial fibroblasts [ 36 ] were reported. Therefore, we reasoned that a decrease in PTEN expression and its dephosphorylation activity could be directly involved in inhibiting LPS-induced lung fibroblast cell proliferation, differentiation and collagen secretion, and overexpression of PTEN may have potential for pulmonary fibrosis treatment.…”

Section: Discussionsupporting

confidence: 77%

Overexpression of PTEN suppresses lipopolysaccharide-induced lung fibroblast proliferation, differentiation and collagen secretion through inhibition of the PI3-K-Akt-GSK3beta pathway

Deng

et al. 2014

Cell Biosci

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BackgroundAbnormal and uncontrolled proliferation of lung fibroblasts may contribute to pulmonary fibrosis. Lipopolysaccharide (LPS) can induce fibroblast proliferation and differentiation through activation of phosphoinositide3-Kinase (PI3-K) pathway. However, the detail mechanism by which LPS contributes to the development of lung fibrosis is not clearly understood. To investigate the role of phosphatase and tensin homolog (PTEN), a PI3-K pathway suppressor, on LPS-induced lung fibroblast proliferation, differentiation, collagen secretion and activation of PI3-K, we transfected PTEN overexpression lentivirus into cultured mouse lung fibroblasts with or without LPS treatment to evaluate proliferation by MTT and Flow cytometry assays. Expression of PTEN, alpha-smooth muscle actin (alpha-SMA), glycogen synthase kinase 3 beta (GSK3beta) and phosphorylation of Akt were determined by Western-blot or real-time RT-PCR assays. The PTEN phosphorylation activity was measured by a malachite green-based assay. The content of C-terminal propeptide of type I procollagen (PICP) in cell culture supernatants was examined by ELISA.ResultsWe found that overexpression of PTEN effectively increased expression and phosphatase activity of PTEN, and concomitantly inhibited LPS-induced fibroblast proliferation, differentiation and collagen secretion. Phosphorylation of Akt and GSK3beta protein expression levels in the LPS-induced PTEN overexpression transfected cells were significantly lower than those in the LPS-induced non-transfected cells, which can be reversed by the PTEN inhibitor, bpV(phen).ConclusionsCollectively, our results show that overexpression and induced phosphatase activity of PTEN inhibits LPS-induced lung fibroblast proliferation, differentiation and collagen secretion through inactivation of PI3-K-Akt-GSK3beta signaling pathways, which can be abrogated by a selective PTEN inhibitor. Thus, expression and phosphatase activity of PTEN could be a potential therapeutic target for LPS-induced pulmonary fibrosis. Compared with PTEN expression level, phosphatase activity of PTEN is more crucial in affecting lung fibroblast proliferation, differentiation and collagen secretion.

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Section: Discussionsupporting

confidence: 77%

Overexpression of PTEN suppresses lipopolysaccharide-induced lung fibroblast proliferation, differentiation and collagen secretion through inhibition of the PI3-K-Akt-GSK3beta pathway

Deng

et al. 2014

Cell Biosci

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“…Therefore, the use of endotoxin has been recently introduced as a model for the study of inflammatory pain in both animals and humans [18][19][20][21][22][23][24][25]. The administration of LPS produces a significant expression of proinflammatory mediators, like cytokines, chemokines, cyclooxygenase-2 (COX-2), and nitric oxide through activation of toll-like receptor 4 (TLR4) via modulating immune cells [26][27][28]. These inflammatory mediators play a pivotal role in the pathophysiology of many chronic pain conditions and act as a pronociceptive agent via sensitization of peripheral and central nerves [29][30][31].…”

Section: Introductionmentioning

confidence: 99%

Automated home-cage monitoring as a potential measure of sickness behaviors and pain-like behaviors in LPS-treated mice

et al. 2021

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The use of endotoxin, such as lipopolysaccharide (LPS) as a model of sickness behavior, has attracted recent attention. To objectively investigate sickness behavior along with its pain-like behaviors in LPS-treated mice, the behavioral measurement requires accurate methods, which reflects clinical relevance. While reflexive pain response tests have been used for decades for pain assessment, its accuracy and clinical relevance remain problematic. Hence, we used automated home-cage monitoring LABORAS to evaluate spontaneous locomotive behaviors in LPS-induced mice. LPS-treated mice displayed sickness behaviors including pain-like behaviors in automated home-cage monitoring characterized by decreased mobile behaviors (climbing, locomotion, rearing) and increased immobility compared to that of the control group in both short- and long-term locomotive assessments. Here, in short-term measurement, both in the open-field test and automated home-cage monitoring, mice demonstrated impaired locomotive behaviors. We also assessed 24 h long-term locomotor activity in the home-cage system, which profiled the diurnal behaviors of LPS-stimulated mice. The results demonstrated significant behavioral impairment in LPS-stimulated mice compared to the control mice in both light and dark phases. However, the difference is more evident in the dark phase compared to the light phase owing to the nocturnal activity of mice. In addition, the administration of indomethacin as a pharmacological intervention improved sickness behaviors in the open-field test as well as automated home-cage monitoring, confirming that automated home-cage monitoring could be potentially useful in pharmacological screening. Together, our results demonstrate that automated home-cage monitoring could be a feasible alternative to conventional methods, such as the open-field test and combining several behavioral assessments may provide a better understanding of sickness behavior and pain-like behaviors in LPS-treated mice.

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“…There is controversy concerning the role of PTEN in regulating the actions of TIR adaptors. Although macrophages from both PTEN heterozygous mice and mice specifically deficient in PTEN in myeloid cells are less responsive to TLR4 or TLR5 ligands (14,15), pharmacological inhibition of PTEN enhances TLR-mediated cytokine production (16). In addition, myeloid-specific PTEN deficiency leads to increased susceptibility to lung infection by Gram-negative and Gram-positive bacteria (17,18).…”

Section: Introductionmentioning

confidence: 99%

Nuclear PTEN enhances the maturation of a microRNA regulon to limit MyD88-dependent susceptibility to sepsis

et al. 2018

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Inhibition of LPS-induced cyclooxygenase 2 and nitric oxide production by transduced PEP-1-PTEN fusion protein in Raw 264.7 macrophage cells

Cited by 9 publications

References 52 publications

Overexpression of PTEN suppresses lipopolysaccharide-induced lung fibroblast proliferation, differentiation and collagen secretion through inhibition of the PI3-K-Akt-GSK3beta pathway

Overexpression of PTEN suppresses lipopolysaccharide-induced lung fibroblast proliferation, differentiation and collagen secretion through inhibition of the PI3-K-Akt-GSK3beta pathway

Automated home-cage monitoring as a potential measure of sickness behaviors and pain-like behaviors in LPS-treated mice

Nuclear PTEN enhances the maturation of a microRNA regulon to limit MyD88-dependent susceptibility to sepsis

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