Cross-talk between the transcription factor Sp1 and C/EBPβ modulates TGFβ1 production to negatively regulate the expression of chemokine RANTES

Arisa Sakamoto; Rui Yamaguchi; Reona Yamaguchi; Shinji Narahara; Hiroyuki Sugiuchi; Yasuo Yamaguchi

Heliyon (Jul 2018)

Cross-talk between the transcription factor Sp1 and C/EBPβ modulates TGFβ1 production to negatively regulate the expression of chemokine RANTES

Arisa Sakamoto,
Rui Yamaguchi,
Reona Yamaguchi,
Shinji Narahara,
Hiroyuki Sugiuchi,
Yasuo Yamaguchi

Affiliations

Arisa Sakamoto: Graduate School of Medical Science, Kumamoto Health Science University, Kitaku Izumi-machi 325, Kumamoto 861-5598, Japan
Rui Yamaguchi: Graduate School of Medical Science, Kumamoto Health Science University, Kitaku Izumi-machi 325, Kumamoto 861-5598, Japan
Reona Yamaguchi: Department of Neuroscience, Graduate School of Medicine, Kyoto University, Yoshida-konoe-cho Sakyo-ku, Kyoto 606-8501, Japan
Shinji Narahara: Graduate School of Medical Science, Kumamoto Health Science University, Kitaku Izumi-machi 325, Kumamoto 861-5598, Japan
Hiroyuki Sugiuchi: Graduate School of Medical Science, Kumamoto Health Science University, Kitaku Izumi-machi 325, Kumamoto 861-5598, Japan
Yasuo Yamaguchi: Graduate School of Medical Science, Kumamoto Health Science University, Kitaku Izumi-machi 325, Kumamoto 861-5598, Japan; Corresponding author.

Journal volume & issue: Vol. 4, no. 7
p. e00679

Abstract

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RANTES is a key chemokine for atherosclerosis, and obesity is associated with progression of atherosclerosis. Substance P (SP) increases glucose uptake and accumulation of lipids in adipocytes, and SP may upregulate RANTES expression. This study investigated the mechanism of RANTES expression by human M1 macrophages stimulated with SP.SP upregulated RANTES protein expression, whereas aprepitant (an NK1R antagonist) blunted this response. Pretreatment of macrophages with BIRB796 (a combined p38γ/p38δ inhibitor) led to a significant decrease of RANTES expression. Next, we investigated the effect of several NK1R internalization factors on RANTES expression, including GRK2, β-arrestin 2, dynamin, ROCK, and TGFβ1. Exposure of macrophages to SP upregulated TGFβ1 expression. Silencing of β-arrestin 2 or GRK2 significantly enhanced the RANTES protein level after stimulation by SP, whereas TGFβ1/2/3 siRNA or dynasore (a dynamin inhibitor) decreased RANTES and Y-27632 (a ROCK inhibitor) had no effect. Surprisingly, silencing of transcription factor specificity protein 1 (Sp1) or inhibition of Sp1 activity by mithramycin led to significant upregulation of TGFβ1 protein and corresponding enhancement of RANTES expression (by ELISA or western blotting), whereas siRNA for C/EBPβ attenuated expression of both TGFβ1 and RANTES. Next, we investigated transcriptional cross-talk among Sp1 and C/EBPβ, TIF1β, or Fli-1 in relation to RANTES expression. Compared with TIF1β or Fli-1 siRNA, C/EBPβ siRNA showed significantly stronger inhibition of RANTES production by Sp1 siRNA-transfected macrophages after stimulation with SP.In conclusion, transcription factor Sp1 engages in cross-talk with C/EBPβ and modulates TGFβ1 production to negatively regulate RANTES expression in macrophages stimulated with SP.In conclusion, cross-talk between the transcription factor Sp1 and C/EBPβ modulates TGFβ1 production to negatively regulate expression of the atherogenic chemokine RANTES in SP-stimulated macrophages, while RANTES is upregulated by SP via the p38γδMAPK/C/EBPβ/TGFβ1 signaling pathway.

Published in Heliyon

ISSN: 2405-8440 (Online)
Publisher: Elsevier
Country of publisher: United Kingdom
LCC subjects: Science: Science (General); Social Sciences: Social sciences (General)
Website: https://www.cell.com/heliyon/home

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