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Differential regulation of RANTES and IL-8 expression in lung adenocarcinoma cells.
Lung Cancer. 2007 May; 56(2):167-74.LC

Abstract

In lung adenocarcinoma, expression of Regulated upon Activation, Normal T cell Expressed and presumably Secreted (RANTES) is a predictor of survival while that of interleukin (IL)-8 is associated with a poor prognosis. In several models, tumorigenesis is abolished by RANTES, while it is facilitated by IL-8. We studied the regulation of RANTES and IL-8 expression in A549 lung adenocarcinoma cells. The effects of tumor necrosis factor (TNF)-alpha and regulators of protein kinases C (PKC)alpha/beta were tested because these have been shown to modulate cancer development and progression. TNF-alpha stimulated expression of both chemokines, while the PKCalpha/beta activator 12-O-tetradecanoyl-phorbol-13-acetate (TPA) induced only expression of IL-8 and inhibited TNF-alpha-induced RANTES expression. The PKCalpha/beta inhibitor Gö 6976 increased TNF-alpha-induced RANTES production and prevented its down-regulation by TPA. In contrast, it decreased TNF-alpha or TPA-induced IL-8 release. The differential regulation of RANTES and IL-8 expression was further analyzed. Site-directed mutagenesis indicated that regulation of RANTES promoter activity required two nuclear factor (NF)-kappaB response elements but not its activator protein (AP)-1 binding sites. An AP-1 and a NF-kappaB recognition sites were necessary for full induction of IL-8 promoter activity by TNF-alpha and TPA. Moreover, electrophoretic mobility shift assays demonstrated that NF-kappaB response elements from the RANTES promoter were of lower affinity than that from the IL-8 promoter. Immunoblotting experiments showed that TPA was more potent than TNF-alpha to induce in a PKCalpha/beta dependent manner the p44/p42 mitogen-activated protein kinases (MAPK) signaling cascade which controls AP-1 activity. Conversely, TPA inhibited TNF-alpha-induced NF-kappaB signaling and was a weak activator of this pathway. Thus, TPA did not sufficiently activate NF-kappaB to increase transcription through the low affinity NF-kappaB binding sites on RANTES promoter and its inhibitory effect on TNF-alpha-induced NF-kappaB signaling resulted in a reduced transcription rate. On IL-8 promoter, increased transcription through the high affinity NF-kappaB binding site occurred even with poorly activated NF-kappaB and the functional AP-1 response element compensated any loss of transcription rate. These data provide a mechanistic insight into the differential regulation of IL-8 and RANTES expression by PKCalpha/beta in lung adenocarcinoma cells.

Authors+Show Affiliations

Institut National de la Santé et de la Recherche Médicale U454-IFR3, 34295 Montpellier cedex 5, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17207890

Citation

Henriquet, Corinne, et al. "Differential Regulation of RANTES and IL-8 Expression in Lung Adenocarcinoma Cells." Lung Cancer (Amsterdam, Netherlands), vol. 56, no. 2, 2007, pp. 167-74.
Henriquet C, Gougat C, Combes A, et al. Differential regulation of RANTES and IL-8 expression in lung adenocarcinoma cells. Lung Cancer. 2007;56(2):167-74.
Henriquet, C., Gougat, C., Combes, A., Lazennec, G., & Mathieu, M. (2007). Differential regulation of RANTES and IL-8 expression in lung adenocarcinoma cells. Lung Cancer (Amsterdam, Netherlands), 56(2), 167-74.
Henriquet C, et al. Differential Regulation of RANTES and IL-8 Expression in Lung Adenocarcinoma Cells. Lung Cancer. 2007;56(2):167-74. PubMed PMID: 17207890.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Differential regulation of RANTES and IL-8 expression in lung adenocarcinoma cells. AU - Henriquet,Corinne, AU - Gougat,Claire, AU - Combes,Audrey, AU - Lazennec,Gwendal, AU - Mathieu,Marc, Y1 - 2007/01/17/ PY - 2006/08/14/received PY - 2006/12/01/revised PY - 2006/12/04/accepted PY - 2007/1/9/pubmed PY - 2007/7/13/medline PY - 2007/1/9/entrez SP - 167 EP - 74 JF - Lung cancer (Amsterdam, Netherlands) JO - Lung Cancer VL - 56 IS - 2 N2 - In lung adenocarcinoma, expression of Regulated upon Activation, Normal T cell Expressed and presumably Secreted (RANTES) is a predictor of survival while that of interleukin (IL)-8 is associated with a poor prognosis. In several models, tumorigenesis is abolished by RANTES, while it is facilitated by IL-8. We studied the regulation of RANTES and IL-8 expression in A549 lung adenocarcinoma cells. The effects of tumor necrosis factor (TNF)-alpha and regulators of protein kinases C (PKC)alpha/beta were tested because these have been shown to modulate cancer development and progression. TNF-alpha stimulated expression of both chemokines, while the PKCalpha/beta activator 12-O-tetradecanoyl-phorbol-13-acetate (TPA) induced only expression of IL-8 and inhibited TNF-alpha-induced RANTES expression. The PKCalpha/beta inhibitor Gö 6976 increased TNF-alpha-induced RANTES production and prevented its down-regulation by TPA. In contrast, it decreased TNF-alpha or TPA-induced IL-8 release. The differential regulation of RANTES and IL-8 expression was further analyzed. Site-directed mutagenesis indicated that regulation of RANTES promoter activity required two nuclear factor (NF)-kappaB response elements but not its activator protein (AP)-1 binding sites. An AP-1 and a NF-kappaB recognition sites were necessary for full induction of IL-8 promoter activity by TNF-alpha and TPA. Moreover, electrophoretic mobility shift assays demonstrated that NF-kappaB response elements from the RANTES promoter were of lower affinity than that from the IL-8 promoter. Immunoblotting experiments showed that TPA was more potent than TNF-alpha to induce in a PKCalpha/beta dependent manner the p44/p42 mitogen-activated protein kinases (MAPK) signaling cascade which controls AP-1 activity. Conversely, TPA inhibited TNF-alpha-induced NF-kappaB signaling and was a weak activator of this pathway. Thus, TPA did not sufficiently activate NF-kappaB to increase transcription through the low affinity NF-kappaB binding sites on RANTES promoter and its inhibitory effect on TNF-alpha-induced NF-kappaB signaling resulted in a reduced transcription rate. On IL-8 promoter, increased transcription through the high affinity NF-kappaB binding site occurred even with poorly activated NF-kappaB and the functional AP-1 response element compensated any loss of transcription rate. These data provide a mechanistic insight into the differential regulation of IL-8 and RANTES expression by PKCalpha/beta in lung adenocarcinoma cells. SN - 0169-5002 UR - https://www.unboundmedicine.com/medline/citation/17207890/Differential_regulation_of_RANTES_and_IL_8_expression_in_lung_adenocarcinoma_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0169-5002(06)00633-7 DB - PRIME DP - Unbound Medicine ER -