title: IL-17A versus IL-17F induced intracellular signal transduction pathways and modulation by IL-17RA and IL-17RC RNA interference in AGS gastric adenocarcinoma cells.
abstract: Inflammatory processes are implicated in gastric cancer development. In contrast, the role of inflammation and proinflammatory cytokines in established cancer remains to be clarified. We investigated the contribution of IL-17A versus IL-17F-mediated intracellular signalling pathways in human gastric adenocarcinoma AGS cells. IL-8 secretion was evaluated by ELISA, mitogen-activated protein kinase (MAPK)(4) by Western blotting, and activator protein 1(AP-1) and nuclear factor kappa B (NFkappaB) by TransAM transcription factor assay or qRT-PCR. IL-17RA and IL-17RC inhibition were achieved by small interfering RNA (siRNA). IL-17A significantly induced activation of all three MAPK (ERK, p38 and JNK) and downstream transcription factors AP-1 and p65 NFkappaB. IL-17F was less potent but induced a significant activation of p65 NFkappaB. Consistently, IL-17A was more potent to induce IL-8 secretion than IL-17F. Inhibition of either IL-17RA or IL-17RC expression via siRNA led to near complete abrogation of IL-17A-mediated c-Jun and p65 activation. These data suggest that in gastric cancer, absence of either IL-17RA or IL-17RC can inhibit IL-17 responsiveness. Conversely, downstream of IL-17R binding, IL-17A and IL-17F induce key signal transduction pathways implicated in inflammation and carcinogenesis. IL-17A, and possibly IL-17F, may contribute to amplification and persistence of inflammatory processes implicated in inflammation-associated cancer.
authors.affiliation: Department of Immunology & Rheumatology, Mixed Unit Hospices Civils de Lyon-BioMérieux, E. Herriot Hospital, 69437 Lyon Cedex 03, France.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Myew-Ling
authors.initials: ML
authors.lastname: Toh
authors.forename: Saloua
authors.initials: S
authors.lastname: Zrioual
authors.forename: Pierre
authors.initials: P
authors.lastname: Miossec
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D016762:Genes, fos / Q000187:drug effects; D016758:Genes, jun / Q000187:drug effects; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism / Q000494:pharmacology*; D016209:Interleukin-8 / Q000096:biosynthesis; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors* / Q000235:genetics; D053722:Receptors, Interleukin-17 / Q000037:antagonists & inhibitors* / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: C508606:CXCL8 protein, human; D017931:DNA Primers; D004273:DNA, Neoplasm; C508717:IL17A protein, human; C440021:IL17F protein, human; C109985:IL17RA protein, human; C448419:IL17RC protein, human; D020381:Interleukin-17; D016209:Interleukin-8; D016328:NF-kappa B; D034741:RNA, Small Interfering; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17; D011994:Recombinant Proteins; D018808:Transcription Factor AP-1