Transcriptional and posttranscriptional regulation of CXCL8/IL-8 gene expression induced by connective tissue growth factor

Abstract

Connective tissue growth factor (CTGF), a CCN family member, is a secreted protein regulating cellular functions, including fibrosis, apoptosis, adhesion, migration, differentiation, proliferation, angiogenesis, and chondrogenesis. CTGF increases proinflammatory factor production; however, inflammatory cytokine regulation by CTGF is poorly understood. The aim of this study was to identify novel biological functions and elucidate the functional mechanisms of CTGF. Specifically, the study focused on the ability of CTGF-primed monocytes to secrete interleukin 8 (CXCL8/IL-8) and determined the signaling pathways involved in CTGF-induced CXCL8/IL-8 gene regulation during inflammation. We transfected wild-type or mutant CXCL8/IL-8 promoter-derived luciferase reporter constructs into 293T cells to examine the effect of CTGF on the CXCL8/IL-8 promoter. The results showed that the activator protein-1 and nuclear factor κB binding sites of the CXCL8/IL-8 promoter are essential for CTGF-induced CXCL8/IL-8 transcription. Moreover, the CTGF-induced activation of p38 mitogen-activated protein kinase (MAPK), c-Jun-N-terminal kinase, and extracellular signal-regulated kinase (ERK) is involved in this process. In addition, adenosine-uridine-rich elements (AREs) of the CXCL8/IL-8 3'-untranslated region (3'-UTR) reduce CXCL8/IL-8 mRNA stability. To investigate whether CTGF regulates CXCL8/IL-8 gene expression at the posttranscriptional level, we transfected 293 cells with serial luciferase constructs containing different segments of the CXCL8/IL-8 3'-UTR and then stimulated the cells with CTGF. The results suggested that CTGF stabilized luciferase mRNA and increased luciferase activity by regulating the CXCL8/IL-8 3'-UTR. Moreover, the p38 MAPK pathway may contribute to CTGF-induced CXCL8/IL-8 mRNA stabilization.

Vemurafenib and trametinib reduce expression of CTGF and IL-8 in V600EBRAF melanoma cells

“…Lin et al have shown that CTGF regulates CXCL8 promoter via NF-κB signaling. 38 As CTGF and CXCL8 were concomitantly downregulated by vemurafenib and trametinib, we assumed that CTGF might contribute to increased CXCL8 expression also in melanoma. However, our results revealed that CTGF neither influenced CXCL8 expression nor NF-κB activity in melanoma cells.…”

Interleukin (IL)-1β Is a Strong Inducer of IL-36γ Expression in Human Colonic Myofibroblasts

“…As a limitation, we could not show direct evidence that IL-1β induced the binding of NF-κB and AP-1 to the IL-36γ promoter region. So, possible contribution of other mechanisms, such as MAPKs-mediated post-transcriptional mechanism reported in IL-8 mRNA expression [ 34 ], should be investigated in the future. Taken together, it was suggested that NF-κB and AP-1 play a critical role in IL-1β-induced IL-36γ expression in colonic myofibroblasts.…”

Glucose impairs tamoxifen responsiveness modulating connective tissue growth factor in breast cancer cells

“…Of note, a higher expression of CTGF has been also shown in diabetes [ 30 ]. CTGF is strongly up-regulated in disorders, frequently developed by diabetic patients, like cardiovascular disease, nephropathy, neuropathy, and retinopathy [ 36 ]. In line with this, CTGF has been reported as strongly expressed in glomeruli of diabetic patients and animals with nephropathy [ 37 ].…”