title: Carbon monoxide releasing molecule-2 ameliorates IL-1β-induced IL-8 in human gastric cancer cells.
abstract: Carbon monoxide (CO), a byproduct of heme oxygenase (HO), presents antioxidant, anti-inflammatory, and anti-tumor properties. Accumulating evidence supports that interleukin (IL)-8 contribute to the vascularity of human gastric cancer. However, the inhibition of IL-8 expression by CO is yet to be elucidated. Here, we utilized CO releasing molecule-2 (CORM-2) to investigate the effect of CO on IL-1β-induced IL-8 expression and the underlying molecular mechanisms in human gastric cancer AGS cells. CORM-2 dose-dependently suppressed IL-1β-induced IL-8 mRNA and protein expression as well as IL-8 promoter activity. IL-1β induced the translocation of p47(phox) to activate reactive oxygen species (ROS)-producing NADPH oxidase (NOX). Moreover, IL-1β activated MAPKs (Erk1/2, JNK1/2, and p38 MAPK) and promoted nuclear factor (NF)-кB and activator protein (AP)-1 binding activities. Pharmacological inhibition and mutagenesis studies indicated that NOX, ROS, Erk1/2, and p38 MAPK are involved in IL-1β-induced IL-8 expression. Transient transfection of deletion mutant constructs of the IL-8 promoter in cells suggested that NF-кB and AP-1 are critical for IL-1β-induced IL-8 transcription. NOX-derived ROS and MAPKs (Erk1/2 and p38 MAPK) functioned as upstream activators of NF-κB and AP-1, respectively. CORM-2 pretreatment significantly mitigated IL-1β-induced activation of ROS/NF-кB and Erk1/2/AP-1 cascades, blocking IL-8 expression and thus significantly reducing endothelial cell proliferation in the tumor microenvironment.
authors.affiliation: Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea.
authors.forename: Sen
authors.initials: S
authors.lastname: Lian
authors.affiliation: Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea.
authors.forename: Trong Thuan
authors.initials: TT
authors.lastname: Ung
authors.affiliation: Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea.
authors.forename: Pham Ngoc
authors.initials: PN
authors.lastname: Khoi
authors.affiliation: Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea.
authors.forename: Hyun Joong
authors.initials: HJ
authors.lastname: Yoon
authors.affiliation: Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea.
authors.forename: Nam Ho
authors.initials: NH
authors.lastname: Kim
authors.affiliation: Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea.
authors.forename: Kyung Keun
authors.initials: KK
authors.lastname: Kim
authors.affiliation: Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 501-190, Republic of Korea. Electronic address: ydjung@chonnam.ac.kr.
authors.forename: Young Do
authors.initials: YD
authors.lastname: Jung
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000963:Antimetabolites / Q000633:toxicity; D002248:Carbon Monoxide / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D053583:Interleukin-1beta / Q000633:toxicity*; D016209:Interleukin-8 / Q000037:antagonists & inhibitors*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019255:NADPH Oxidases / Q000378:metabolism; D009942:Organometallic Compounds / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013274:Stomach Neoplasms / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000963:Antimetabolites; C508606:CXCL8 protein, human; D053583:Interleukin-1beta; D016209:Interleukin-8; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; C447082:tricarbonyldichlororuthenium (II) dimer; D002248:Carbon Monoxide; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Angiogenesis; Carbon monoxide; Gastric cancer; IL-1β; IL-8