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Macrophages promote benzopyrene-induced tumor transformation of human bronchial epithelial cells by activation of NF-κB and STAT3 signaling in a bionic airway chip culture and in animal models.

Li E, Xu Z, Zhao H, Sun Z, Wang L, Guo Z, Zhao Y, Gao Z, Wang Q - Oncotarget (2015)

Bottom Line: Blockage of interleukin (IL)-6 or tumor necrosis factor (TNF)-α signaling or inhibition of NF-κB, STAT3, or cyclinD1 expression abrogated the effect of macrophages on malignant transformation in the bionic airway chip culture.Similarly, blockage of NF-κB, STAT3, or cyclinD1 using siRNA transfection decreased the carcinogen-induced tumorigenesis in rats.We demonstrated that macrophages are critical in promoting lung tumorigenesis and that the macrophage-initiated TNF-α/NF-κB/cyclinD1 and IL-6/STAT3/cyclinD1 pathways are primarily responsible for promoting lung tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Respiratory Medicine, The Second Affiliated Hospital, Dalian Medical University, Dalian, China.

ABSTRACT
We investigated the role of macrophages in promoting benzopyrene (BaP)-induced malignant transformation of human bronchial epithelial cells using a BaP-induced tumor transformation model with a bionic airway chip in vitro and in animal models. The bionic airway chip culture data showed that macrophages promoted BaP-induced malignant transformation of human bronchial epithelial cells, which was mediated by nuclear factor (NF)-κB and STAT3 pathways to induce cell proliferation, colony formation in chip culture, and tumorigenicity in nude mice. Blockage of interleukin (IL)-6 or tumor necrosis factor (TNF)-α signaling or inhibition of NF-κB, STAT3, or cyclinD1 expression abrogated the effect of macrophages on malignant transformation in the bionic airway chip culture. In vivo, macrophages promoted lung tumorigenesis in a carcinogen-induced animal model. Similarly, blockage of NF-κB, STAT3, or cyclinD1 using siRNA transfection decreased the carcinogen-induced tumorigenesis in rats. We demonstrated that macrophages are critical in promoting lung tumorigenesis and that the macrophage-initiated TNF-α/NF-κB/cyclinD1 and IL-6/STAT3/cyclinD1 pathways are primarily responsible for promoting lung tumorigenesis.

No MeSH data available.


Related in: MedlinePlus

Illustration of the bionic airway chipA, Illustration of the airway structure and biomimetic model, including three vertical compartments with two different types of cells separated by porous membranes. B, Configuration of the bionic airway chip. The main body of the chip contains two polydimethylsiloxane layers and a piece of porous membrane. Sterile air and culture media flow in the top and bottom channels, respectively. The bronchial epithelial cells were grown on the top of the membrane, while the macrophages were grown on the opposite site of the porous membrane.
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Figure 1: Illustration of the bionic airway chipA, Illustration of the airway structure and biomimetic model, including three vertical compartments with two different types of cells separated by porous membranes. B, Configuration of the bionic airway chip. The main body of the chip contains two polydimethylsiloxane layers and a piece of porous membrane. Sterile air and culture media flow in the top and bottom channels, respectively. The bronchial epithelial cells were grown on the top of the membrane, while the macrophages were grown on the opposite site of the porous membrane.

Mentions: To mimic the cell compartmentalization of the airway in humans (Fig. 1A), we fabricated a working biomimetic airway chip. The main body of the chip consisted of three parts: two polydimethylsiloxane (PDMS) layers (the top and bottom layers) and one porous membrane layer (the middle layer) (Fig. 1B). The PDMS microfluidic chip was fabricated using a Sylgard 184 kit (Dow Corning, Midland, TX, USA) by a standard soft lithography method. Briefly, two PDMS layers were fabricated by replica molding against masters, and a 5-μm pore polycarbonate membrane (Nuclepore, Whatman, Buckinghamshire, UK) was bonded using wet aminosilanization of the membrane and contact binding with oxygen plasma-treated PDMS (150 mTorr, 50 W, 25 s). The microfabricated device was then continuously supplied with air and cell growth medium to mimic the real microenvironment of the bronchi in human lungs. The human bronchial epithelial cell line 16HBE (obtained from the Chinese Academy of Medical Sciences, Beijing, China) and macrophages were cultured on the top and bottom of the porous membrane, respectively. The ratio of 16HBE cells and macrophages was 10:1 (16HBE cells/macrophages). The upper channel pumped sterile air, and the bottom channel simultaneously pumped cell culture medium using a syringe pump.


Macrophages promote benzopyrene-induced tumor transformation of human bronchial epithelial cells by activation of NF-κB and STAT3 signaling in a bionic airway chip culture and in animal models.

Li E, Xu Z, Zhao H, Sun Z, Wang L, Guo Z, Zhao Y, Gao Z, Wang Q - Oncotarget (2015)

Illustration of the bionic airway chipA, Illustration of the airway structure and biomimetic model, including three vertical compartments with two different types of cells separated by porous membranes. B, Configuration of the bionic airway chip. The main body of the chip contains two polydimethylsiloxane layers and a piece of porous membrane. Sterile air and culture media flow in the top and bottom channels, respectively. The bronchial epithelial cells were grown on the top of the membrane, while the macrophages were grown on the opposite site of the porous membrane.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496191&req=5

Figure 1: Illustration of the bionic airway chipA, Illustration of the airway structure and biomimetic model, including three vertical compartments with two different types of cells separated by porous membranes. B, Configuration of the bionic airway chip. The main body of the chip contains two polydimethylsiloxane layers and a piece of porous membrane. Sterile air and culture media flow in the top and bottom channels, respectively. The bronchial epithelial cells were grown on the top of the membrane, while the macrophages were grown on the opposite site of the porous membrane.
Mentions: To mimic the cell compartmentalization of the airway in humans (Fig. 1A), we fabricated a working biomimetic airway chip. The main body of the chip consisted of three parts: two polydimethylsiloxane (PDMS) layers (the top and bottom layers) and one porous membrane layer (the middle layer) (Fig. 1B). The PDMS microfluidic chip was fabricated using a Sylgard 184 kit (Dow Corning, Midland, TX, USA) by a standard soft lithography method. Briefly, two PDMS layers were fabricated by replica molding against masters, and a 5-μm pore polycarbonate membrane (Nuclepore, Whatman, Buckinghamshire, UK) was bonded using wet aminosilanization of the membrane and contact binding with oxygen plasma-treated PDMS (150 mTorr, 50 W, 25 s). The microfabricated device was then continuously supplied with air and cell growth medium to mimic the real microenvironment of the bronchi in human lungs. The human bronchial epithelial cell line 16HBE (obtained from the Chinese Academy of Medical Sciences, Beijing, China) and macrophages were cultured on the top and bottom of the porous membrane, respectively. The ratio of 16HBE cells and macrophages was 10:1 (16HBE cells/macrophages). The upper channel pumped sterile air, and the bottom channel simultaneously pumped cell culture medium using a syringe pump.

Bottom Line: Blockage of interleukin (IL)-6 or tumor necrosis factor (TNF)-α signaling or inhibition of NF-κB, STAT3, or cyclinD1 expression abrogated the effect of macrophages on malignant transformation in the bionic airway chip culture.Similarly, blockage of NF-κB, STAT3, or cyclinD1 using siRNA transfection decreased the carcinogen-induced tumorigenesis in rats.We demonstrated that macrophages are critical in promoting lung tumorigenesis and that the macrophage-initiated TNF-α/NF-κB/cyclinD1 and IL-6/STAT3/cyclinD1 pathways are primarily responsible for promoting lung tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Respiratory Medicine, The Second Affiliated Hospital, Dalian Medical University, Dalian, China.

ABSTRACT
We investigated the role of macrophages in promoting benzopyrene (BaP)-induced malignant transformation of human bronchial epithelial cells using a BaP-induced tumor transformation model with a bionic airway chip in vitro and in animal models. The bionic airway chip culture data showed that macrophages promoted BaP-induced malignant transformation of human bronchial epithelial cells, which was mediated by nuclear factor (NF)-κB and STAT3 pathways to induce cell proliferation, colony formation in chip culture, and tumorigenicity in nude mice. Blockage of interleukin (IL)-6 or tumor necrosis factor (TNF)-α signaling or inhibition of NF-κB, STAT3, or cyclinD1 expression abrogated the effect of macrophages on malignant transformation in the bionic airway chip culture. In vivo, macrophages promoted lung tumorigenesis in a carcinogen-induced animal model. Similarly, blockage of NF-κB, STAT3, or cyclinD1 using siRNA transfection decreased the carcinogen-induced tumorigenesis in rats. We demonstrated that macrophages are critical in promoting lung tumorigenesis and that the macrophage-initiated TNF-α/NF-κB/cyclinD1 and IL-6/STAT3/cyclinD1 pathways are primarily responsible for promoting lung tumorigenesis.

No MeSH data available.


Related in: MedlinePlus