PMID- 32302067
OWN - NLM
STAT- MEDLINE
DCOM- 20210402
LR  - 20240328
IS  - 2052-1707 (Electronic)
IS  - 2052-1707 (Linking)
VI  - 8
IP  - 2
DP  - 2020 Apr
TI  - beta2-adrenergic stimulation induces interleukin-6 by increasing Arid5a, a 
      stabilizer of mRNA, through cAMP/PKA/CREB pathway in cardiac fibroblasts.
PG  - e00590
LID - 10.1002/prp2.590 [doi]
LID - e00590
AB  - BACKGROUND AND PURPOSE: In cardiovascular diseases, cardiac fibroblasts (CFs) 
      participate in the myocardial inflammation by producing pro-inflammatory 
      cytokines, worsening the prognosis. beta2-adrenergic receptor (AR) and beta3AR are 
      expressed in CFs, and beta-adrenergic stimulation promotes CFs to produce 
      pro-inflammatory cytokines. However, the mechanism of the expression of 
      pro-inflammatory cytokines in response to beta-adrenergic stimulation remains to be 
      fully elucidated. EXPERIMENTAL APPROACH: CFs were isolated from adult wild-type 
      or AT-rich interactive domain-containing protein 5A (Arid5a) knockout mice. The 
      expression of mRNA was measured by real-time RT-PCR. Interleukin (IL)-6 protein 
      was measured by ELISA. The activity of nuclear factor-kappaB (NF-kappaB) and cyclic AMP 
      (cAMP) response element binding protein (CREB) was assessed by ELISA-like assay 
      or Western blotting. KEY RESULTS: The beta-adrenergic stimulation remarkably induced 
      IL-6 mRNA and protein through beta2AR in CFs. The activation of adenylate cyclase 
      and the enhancement of intracellular cAMP resulted in the upregulation of IL-6 
      mRNA expression. The induction of IL-6 transcript by beta2AR signaling was 
      independent of NF-kappaB. Concomitant with IL-6, the expression of Arid5a, an IL-6 
      mRNA stabilizing factor, was enhanced by beta2-adrenergic stimulation and by cAMP 
      increase. Importantly, beta2AR signaling-mediated IL-6 induction was suppressed in 
      Arid5a knockout CFs. Finally, beta2AR stimulation phosphorylated CREB via PKA 
      pathway, and the activation of CREB was essential for the induction of Arid5a and 
      IL-6 mRNA. CONCLUSION AND IMPLICATIONS: beta2-adrenergic stimulation 
      post-transcriptionally upregulates the expression of IL-6 by the induction of 
      Arid5a through cAMP/PKA/CREB pathway in adult CFs. beta2AR/Arid5a/IL-6 axis could be 
      a therapeutic target against cardiac inflammation.
CI  - (c) 2020 The Authors. Pharmacology Research & Perspectives published by John Wiley 
      & Sons Ltd, British Pharmacological Society and American Society for Pharmacology 
      and Experimental Therapeutics.
FAU - Tanaka, Shota
AU  - Tanaka S
AUID- ORCID: 0000-0002-3053-6928
AD  - Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical 
      Sciences, Osaka University, Suita City, Osaka, Japan.
FAU - Imaeda, Atsuki
AU  - Imaeda A
AD  - Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical 
      Sciences, Osaka University, Suita City, Osaka, Japan.
FAU - Matsumoto, Kotaro
AU  - Matsumoto K
AD  - Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical 
      Sciences, Osaka University, Suita City, Osaka, Japan.
FAU - Maeda, Makiko
AU  - Maeda M
AD  - Project of Clinical Pharmacology and Therapeutics, Graduate School of 
      Pharmaceutical Sciences, Osaka University, Suita City, Osaka, Japan.
FAU - Obana, Masanori
AU  - Obana M
AD  - Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical 
      Sciences, Osaka University, Suita City, Osaka, Japan.
FAU - Fujio, Yasushi
AU  - Fujio Y
AD  - Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical 
      Sciences, Osaka University, Suita City, Osaka, Japan.
AD  - Project of Clinical Pharmacology and Therapeutics, Graduate School of 
      Pharmaceutical Sciences, Osaka University, Suita City, Osaka, Japan.
AD  - Integrated Frontier Research for Medical Science Division, Institute for Open and 
      Transdisciplinary Research Initiatives, Osaka University, Suita City, Osaka, 
      Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Pharmacol Res Perspect
JT  - Pharmacology research & perspectives
JID - 101626369
RN  - 0 (Adrenergic beta-Agonists)
RN  - 0 (Arid5a protein, mouse)
RN  - 0 (Creb1 protein, mouse)
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Interleukin-6)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Adrenergic, beta-2)
RN  - 0 (Transcription Factor RelA)
RN  - 0 (Transcription Factors)
RN  - 0 (interleukin-6, mouse)
RN  - E0399OZS9N (Cyclic AMP)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
RN  - L628TT009W (Isoproterenol)
SB  - IM
MH  - Adrenergic beta-Agonists/pharmacology
MH  - Animals
MH  - Cyclic AMP/*metabolism
MH  - Cyclic AMP Response Element-Binding Protein/*metabolism
MH  - Cyclic AMP-Dependent Protein Kinases/*metabolism
MH  - DNA-Binding Proteins/*genetics
MH  - Female
MH  - Fibroblasts/*metabolism
MH  - Interleukin-6/*genetics
MH  - Isoproterenol/pharmacology
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Myocardium/cytology
MH  - RNA, Messenger/metabolism
MH  - Receptors, Adrenergic, beta-2/*metabolism
MH  - Signal Transduction
MH  - Transcription Factor RelA/metabolism
MH  - Transcription Factors/*genetics
PMC - PMC7164407
OTO - NOTNLM
OT  - fibroblasts
OT  - interleukin-6
OT  - beta adrenergic receptor
COIS- The authors have no conflicts of interest associated with this manuscript.
EDAT- 2020/04/18 06:00
MHDA- 2021/04/07 06:00
PMCR- 2020/04/17
CRDT- 2020/04/18 06:00
PHST- 2019/11/06 00:00 [received]
PHST- 2020/03/19 00:00 [revised]
PHST- 2020/03/24 00:00 [accepted]
PHST- 2020/04/18 06:00 [entrez]
PHST- 2020/04/18 06:00 [pubmed]
PHST- 2021/04/07 06:00 [medline]
PHST- 2020/04/17 00:00 [pmc-release]
AID - PRP2590 [pii]
AID - 10.1002/prp2.590 [doi]
PST - ppublish
SO  - Pharmacol Res Perspect. 2020 Apr;8(2):e00590. doi: 10.1002/prp2.590.