title: Interleukin-17 induces AP-1 activity and cellular transformation via upregulation of tumor progression locus 2 activity.
abstract: Inflammatory conditions elicited by extrinsic environmental factors promote malignant transformation, tumor growth and metastasis. Although the role of T cells in cancer promotion has been examined, little is known about the underlying molecular mechanisms of interleukin-17 A (IL-17A), a proinflammatory cytokine produced by activated CD4(+) memory T cells, in carcinogenesis. Here, we report that IL-17A induces neoplastic transformation of JB6 Cl41 cells through activation of tumor progression locus 2 (TPL2). IL-17A dose- and time-dependently increases TPL2 phosphorylation in JB6 Cl41 cells through IL-17A receptor. IL-17A activates  mitogen-activated protein kinase/extracellular signal-regulated kinase kinases, c-jun N-terminal kinases and STAT3 signaling pathways, which are inhibited by a TPL2 kinase inhibitor (TKI). Furthermore, IL-17A activates c-fos and c-jun promoter activity, resulting in increased activator protein-1 (AP-1) activity. When small interfering RNA of IL-17A receptor (IL-17R), IL-17A and TPL2 were introduced into JB6 Cl41 cells, respectively, IL-17A-induced AP-1 activity was significantly decreased compared with control cells. Similarly, TPL2 inhibition suppressed AP-1 activity induced by IL-17A. The knockdown of IL-17R and TKI treatment in JB6 Cl41 cells resulted in decreased IL-17A-induced cell transformation. The in vivo chorioallantoic membrane assay also showed that IL-17A increased tumor formation of JB6 Cl41 cells, whereas TKI inhibited the tumorigenesis promoted by IL-17A. Consistent with these observations, knockdown of IL-17A and/or inhibition of TPL2 attenuated tumorigenicity of human breast cancer MCF7 cells. Together, our findings point to a critical role for the IL-17A-induced TPL2 signaling pathway in supporting cancer-associated inflammation in the tumor microenvironment. Therapeutic approaches that target this pathway may, therefore, effectively inhibit carcinogenesis.
authors.affiliation: BK21 Project Team, College of Pharmacy, Chosun University,  Gwangju 501-759, South Korea.
authors.forename: Garam
authors.initials: G
authors.lastname: Kim
authors.forename: Prem
authors.initials: P
authors.lastname: Khanal
authors.forename: Sung-Chul
authors.initials: SC
authors.lastname: Lim
authors.forename: Hyo Jeong
authors.initials: HJ
authors.lastname: Yun
authors.forename: Sang-Gun
authors.initials: SG
authors.lastname: Ahn
authors.forename: Sung Hwan
authors.initials: SH
authors.lastname: Ki
authors.forename: Hong Seok
authors.initials: HS
authors.lastname: Choi
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002645:Chickens; D049033:Chorioallantoic Membrane; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007124:Immunoenzyme Techniques; D020381:Interleukin-17 / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D053722:Receptors, Interleukin-17 / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D020381:Interleukin-17; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D034741:RNA, Small Interfering; D053722:Receptors, Interleukin-17; D018808:Transcription Factor AP-1; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human