Constitutive nuclear factor kappaB activity is required to elicit interferon-gamma-induced expression of chemokine CXC ligand 9 (CXCL9) and CXCL10 in human tumour cell lines.
CXC ligand 10 (CXCL10) and CXCL9 are chemoattractants for activated T cells and possess angiostatic activity. Both CXCL9 and CXCL10 have been considered as important components for the anti-tumour activities of interferon-gamma (IFNgamma) and interleukin-12 in animal models. In this article we show that the CXCL9 and CXCL10 genes in some types of human tumour cell lines are not inducible by IFNgamma and we describe experiments designed to explore the molecular mechanisms involved in this impaired induction. The human oral squamous carcinoma line Ca9-22 and the glioma line A172 failed to express CXCL9 and CXCL10 mRNAs in response to IFNgamma, whereas other carcinoma lines including HSC-2 did express these mRNAs. Production of these chemokine proteins was also impaired in Ca9-22 cells. The impaired expression was not due to any deficiency in the IFNgamma/signal transducer and activator of transcription 1 (STAT1)-dependent signalling pathway. Instead, analysis of nuclear factor kappaB (NF-kappaB) activity revealed that the constitutive low level of NF-kappaB activity, which is seen in cells that express these chemokines, was absent in Ca9-22 and A172 cells. Activation of NF-kappaB in Ca9-22 cells restored the expression of IFNgamma-stimulated CXCL9 and CXCL10 mRNAs. In contrast, inhibition of the constitutive NF-kappaB in HSC-2 cells by adenovirus-mediated gene transfer of a dominant-negative IkappaBalpha suppressed the IFNgamma-induced expression of the CXCL9 and CXCL10 mRNAs. These results indicate that constitutive NF-kappaB activity, which is often associated with tumour development, is required for the induced expression of CXCL9 and CXCL10 genes in human tumour cell lines in response to IFNgamma.
Hiroi
Miki
M
Department of Basic Dental Science, Center for Molecular Biology, Meikai University School of Dentistry, 1-1 Keyakidai, Sakado, Saitama 350-0283, Japan.
Ohmori
Yoshihiro
Y
D002277:Carcinoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D005910:Glioma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D007371:Interferon-gamma / Q000494:pharmacology*; D009062:Mouth Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism
C080810:CXCL9 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D007371:Interferon-gamma