1-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) attenuates gemcitabine-induced neutrophil extravasation
Abstract Cancer patients treated with chemotherapy often experience a rapid decline of blood neutrophils, a dose-limiting side effect called chemotherapy-induced neutropenia. This complication brings about dose reductions or cessation of chemotherapy during treatment of cancer patients because a rap...
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| Format: | Article |
| Language: | English |
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BMC
2019-01-01
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| Series: | Cell & Bioscience |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13578-018-0266-7 |
| _version_ | 1818559134383996928 |
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| author | Jinseon Jeong Yong-Jae Kim Do Young Lee Byoung-Gon Moon Ki-Young Sohn Sun Young Yoon Jae Wha Kim |
| author_facet | Jinseon Jeong Yong-Jae Kim Do Young Lee Byoung-Gon Moon Ki-Young Sohn Sun Young Yoon Jae Wha Kim |
| author_sort | Jinseon Jeong |
| collection | DOAJ |
| description | Abstract Cancer patients treated with chemotherapy often experience a rapid decline of blood neutrophils, a dose-limiting side effect called chemotherapy-induced neutropenia. This complication brings about dose reductions or cessation of chemotherapy during treatment of cancer patients because a rapid decline of neutrophil counts increases susceptibility to infection. Here, we found that 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) attenuates gemcitabine-induced neutrophil extravasation via the inhibition of neutrophil-attracting chemokine production in macrophages using in vivo and in vitro approaches. A single intraperitoneal administration of gemcitabine induced the migration of circulating neutrophils into the peritoneal cavity in normal mice, and PLAG effectively decreased neutrophil migration by inhibiting the expression of adhesion molecules, L-selectin and LFA-1. Inhibition of CXCR2 by its antagonist, reparixin, abrogated gemcitabine-induced neutrophil migration, indicating that chemokines produced by gemcitabine mainly support neutrophil activation. In vitro experiments demonstrated that PLAG inhibited NADPH oxidase 2 (NOX2)-mediated reactive oxygen species production induced by gemcitabine, which is the upstream of MIP-2 and/or CXCL8. Importantly, PLAG down-regulated gemcitabine-induced membrane translocation of the cytosolic NOX subunit, Rac1, and phosphorylation of p47phox. The activation of upstream signaling molecules of p47phox phosphorylation, phospholipase C β3 and protein kinase C, were effectively regulated by PLAG. We also demonstrated that 1-palmitoyl-2-linoleic-3-hydroxyl-rac-glycerol (PLH), the natural form of diacylglycerol, has no effects on gemcitabine-induced CXCL8 production and dHL-60 migration, suggesting that an acetyl group at the third position of the glycerol backbone may have a key role in the regulation of neutrophil activation. Altogether, this study suggests the potential of PLAG as a therapeutic strategy to modulate chemotherapy-induced neutrophil activation for cancer patients undergoing chemotherapeutic treatment. |
| first_indexed | 2024-12-14T00:21:25Z |
| format | Article |
| id | doaj.art-7c9bfabb1a1344a7bf44910a0f6d6faa |
| institution | Directory Open Access Journal |
| issn | 2045-3701 |
| language | English |
| last_indexed | 2024-12-14T00:21:25Z |
| publishDate | 2019-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell & Bioscience |
| spelling | doaj.art-7c9bfabb1a1344a7bf44910a0f6d6faa2022-12-21T23:25:13ZengBMCCell & Bioscience2045-37012019-01-019111510.1186/s13578-018-0266-71-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) attenuates gemcitabine-induced neutrophil extravasationJinseon Jeong0Yong-Jae Kim1Do Young Lee2Byoung-Gon Moon3Ki-Young Sohn4Sun Young Yoon5Jae Wha Kim6Cell Factory Research Center, Division of Systems Biology and Bioengineering, Korea Research Institute of Bioscience and BiotechnologyDivision of Global New Drug Development, ENZYCHEM LifesciencesDivision of Global New Drug Development, ENZYCHEM LifesciencesDivision of Global New Drug Development, ENZYCHEM LifesciencesDivision of Global New Drug Development, ENZYCHEM LifesciencesDivision of Global New Drug Development, ENZYCHEM LifesciencesCell Factory Research Center, Division of Systems Biology and Bioengineering, Korea Research Institute of Bioscience and BiotechnologyAbstract Cancer patients treated with chemotherapy often experience a rapid decline of blood neutrophils, a dose-limiting side effect called chemotherapy-induced neutropenia. This complication brings about dose reductions or cessation of chemotherapy during treatment of cancer patients because a rapid decline of neutrophil counts increases susceptibility to infection. Here, we found that 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) attenuates gemcitabine-induced neutrophil extravasation via the inhibition of neutrophil-attracting chemokine production in macrophages using in vivo and in vitro approaches. A single intraperitoneal administration of gemcitabine induced the migration of circulating neutrophils into the peritoneal cavity in normal mice, and PLAG effectively decreased neutrophil migration by inhibiting the expression of adhesion molecules, L-selectin and LFA-1. Inhibition of CXCR2 by its antagonist, reparixin, abrogated gemcitabine-induced neutrophil migration, indicating that chemokines produced by gemcitabine mainly support neutrophil activation. In vitro experiments demonstrated that PLAG inhibited NADPH oxidase 2 (NOX2)-mediated reactive oxygen species production induced by gemcitabine, which is the upstream of MIP-2 and/or CXCL8. Importantly, PLAG down-regulated gemcitabine-induced membrane translocation of the cytosolic NOX subunit, Rac1, and phosphorylation of p47phox. The activation of upstream signaling molecules of p47phox phosphorylation, phospholipase C β3 and protein kinase C, were effectively regulated by PLAG. We also demonstrated that 1-palmitoyl-2-linoleic-3-hydroxyl-rac-glycerol (PLH), the natural form of diacylglycerol, has no effects on gemcitabine-induced CXCL8 production and dHL-60 migration, suggesting that an acetyl group at the third position of the glycerol backbone may have a key role in the regulation of neutrophil activation. Altogether, this study suggests the potential of PLAG as a therapeutic strategy to modulate chemotherapy-induced neutrophil activation for cancer patients undergoing chemotherapeutic treatment.http://link.springer.com/article/10.1186/s13578-018-0266-7PLAGGemcitabineChemotherapy induced neutropenia (CIN)ChemokineReactive oxygen speciesNADPH oxidase 2 |
| spellingShingle | Jinseon Jeong Yong-Jae Kim Do Young Lee Byoung-Gon Moon Ki-Young Sohn Sun Young Yoon Jae Wha Kim 1-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) attenuates gemcitabine-induced neutrophil extravasation Cell & Bioscience PLAG Gemcitabine Chemotherapy induced neutropenia (CIN) Chemokine Reactive oxygen species NADPH oxidase 2 |
| title | 1-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) attenuates gemcitabine-induced neutrophil extravasation |
| title_full | 1-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) attenuates gemcitabine-induced neutrophil extravasation |
| title_fullStr | 1-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) attenuates gemcitabine-induced neutrophil extravasation |
| title_full_unstemmed | 1-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) attenuates gemcitabine-induced neutrophil extravasation |
| title_short | 1-Palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) attenuates gemcitabine-induced neutrophil extravasation |
| title_sort | 1 palmitoyl 2 linoleoyl 3 acetyl rac glycerol plag attenuates gemcitabine induced neutrophil extravasation |
| topic | PLAG Gemcitabine Chemotherapy induced neutropenia (CIN) Chemokine Reactive oxygen species NADPH oxidase 2 |
| url | http://link.springer.com/article/10.1186/s13578-018-0266-7 |
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