Insulin-like growth factor-I augments interleukin-8 promoter activity through induction of activator protein-1 complex formation.
We previously established that stimulation by IGF-I of interleukin (IL)-8 expression in leukocytes required activation of extracellular-regulated kinase (ERK) and basal activity of c-Jun N-terminal kinase (JNK). In this study, we tested the hypothesis that IGF-I stimulates IL-8 expression at the transcriptional level through induction of Fos/Jun activator protein (AP)-1 complex formation. Inhibition studies using the transcriptional inhibitor actinomycin D and IL-8 promoter activation studies indicate that IGF-I act at the transcriptional level. Using gel shift assays we demonstrate that IGF-I induces the formation of active c-Jun/c-Fos AP-1 complexes. Promoter activation studies using mutated IL-8 promoter constructs show that the AP-1 response element is required for promoter activation by IGF-I whereas CAAT-enhancer binding protein (C/EBP) and nuclear factor of kappa B (NFkappaB) sites were not essential. These results indicate that IGF-I can augment IL-8 expression through activation of AP-1 independent of other inducible transcription factors which have shown to be involved in IL-8 regulation by immune stimuli. This finding is in agreement with our previous observation that IGF-I is able to enhance basal IL-8 production in peripheral blood mononuclear cells (PBMC) in the absence of other stimuli.
Kooijman
Ron
R
Department of Pharmacology, Medical School, Free University of Brussels (VUB), Laarbeeklaan 103, B-1090 Jette, Belgium. ron.kooijman@vub.ac.be
Coppens
Astrid
A
Van den Keybus
Catherine
C
D002460:Cell Line; D003609:Dactinomycin / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D016209:Interleukin-8 / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D016209:Interleukin-8; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D003609:Dactinomycin; D007334:Insulin-Like Growth Factor I