Autocrine and Paracrine Regulation of Interleukin-8 Expression in Lung Cancer Cells

Abstract

We had previously demonstrated that lung cancer cells, upon contact with macrophages, could be induced to secrete angiogenic factors to promote tumor angiogenesis. In this study, we focused on the paracrine and autocrine regulation of interleukin (IL)-8 expression in sensitized lung cancer cells after interacting with macrophages. We found that the IL-8 mRNA expression in lung cancer cells significantly increased after coculture with phorbol myristate acetate-treated THP-1 cells and human primary lung macrophages. Fresh lung cancer CL1-5 cells cocultured with macrophage-sensitized lung cancer cells still had a 35% of increase in IL-8 mRNA expression. The addition of anti-inflammatory agents pyrrolidine dithiocarbamate, pentoxifylline, aspirin, and dexamethasone could completely suppress the expression of IL-8 mRNA in fresh/sensitized lung cancer cell cocultures. Human recombinant tumor necrosis factor (TNF)-alpha and IL-1alpha could induce IL-8 expression in lung cancer cells in a dose-dependent manner. Neutralization with TNF-alpha and IL-1alpha antibodies in cocultures decreased the levels of IL-8 expression in sensitized lung cancer cells. Nuclear factor-kappaB transcriptional activity was also suppressed by the same antibodies, as confirmed by a reporter gene assay and the electrophoretic mobility shift assay. Our results highly suggest that both autocrine and paracrine regulation are involved in IL-8 expression of lung cancer cells cocultured with macrophage. Also, the regulations of IL-8 expression in lung cancer cells were through the nuclear factor-kappaB pathway and modulated by TNF-alpha and IL-1alpha.

Areca nut exposure increases secretion of tumor‐promoting cytokines in gingival fibroblasts that trigger DNA damage in oral keratinocytes

“…For instance, GRO‐α is a potential mediator of cancer invasion in several human cancers such as gastric cancer26 and colon adenocarcinoma 27. IL‐8 is capable of promoting cancer progression by regulating angiogenesis through autocrine and paracrine mechanisms 28, 29. Autocrine effects of IL‐6 in tumorigenesis have been identified in human cancers such as prostatic,30 breast9 and head and neck cancer 31.…”

Anticancer effects of tanshinone I in human non-small cell lung cancer

“…Some nonsteroidal anti-inflammatory drugs, such as aspirin, can reduce the risk of developing colorectal and breast cancers (16), and selective cyclooxygenase-2 inhibitors can inhibit angiogenesis in vitro (36). Our previous studies have shown that several anti-inflammatory agents can effectively suppress the expression of the angiogenic factor IL-8 (11,31). In the present study, we investigated the anti-inflammatory, antitumorigenic, and antimetastatic effects of three major bioactive compounds contained in Danshen, including tanshinone I, tanshinone IIA, and cryptotanshinone in NSCLC.…”

“…The constructions of the IL-8 proximal promoter, the sitedirected mutagenesis of the IL-8 activator protein-1 (AP-1), nuclear factor (NF)-IL-6, and NF-nB sites (31), as well as vascular endothelial growth factor (VEGF) promoter, a gift from Dr. Ann (32), are used for luciferase reporter assay. Briefly, 5 Â 10 4 CL1-5 cells were cotransfected with the individual IL-8 promoter or VEGF promoter construct and a pSV-h-galactosidase plasmid (Promega) with Lipofect-AMINE (Invitrogen), and the cells were treated with tanshinone I, tanshinone IIA, or cryptotanshinone at the designated concentrations for 24 h. The cell lysate was harvested and the genes were identified by luciferase activity using the Dual-Light Luciferase Reporter Gene Assay System (Invitrogen).…”

“…Oligonucleotides were labeled with digoxigenin-11-dUTP (Roche Molecular Biochemicals) using Klenow polymerase (Invitrogen) and purified by MicroSpin G-50 columns (Amersham Pharmacia). The details of nuclear extract preparation, electrophoresis, and detection have been described previously (11,31).…”

Tumor Necrosis Factor-α- and Interleukin-1-Induced Cellular Responses: Coupling Proteomic and Genomic Information

“…10 In response to activation by either bacterial products (lipopolysaccharide, LPS) or foreign particles, circulating macrophages secrete TNFα, an initiator of the innate immune response. In a paracrine manner, TNFα induces surrounding cells to produce interleukin-8 (to elicit phagocyte recruitment) 11 and E-selectin (to promote phagocytic cell adhesion to the surrounding endothelium).12 Autocrine action by TNFα promotes additional TNFα production13 as well as the production and release of IL-1 by macrophages.14 In a paracrine manner, IL-1 induces the local production of Interleukin-615 and the expression of Intercellular Adhesion Molecule-1 (ICAM-1). 16 Together, these and other protein products induced by TNFα and IL-1 mediate the innate immune response and lead to activation of the adaptive immune response.…”