Cyclic AMP response element-binding protein is implicated in IL-6 production from arthritic synovial cells

Ishizu, Akihiro; Abe, Asami; Miyatake, Yukiko; Baba, Tomohisa; Iinuma, Chihiro; Tomaru, Utano; Yoshiki, Takashi

doi:10.3109/s10165-009-0245-2

Cited by 5 publications

(3 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…They cooperate to recruit CBP at the IL‐6 promoter, thus enable synergistic gene activation. In consistent with previous reports [Miyazawa et al, 1999; Bergamaschi et al, 2006; Ishizu et al, 2010; Spooren et al, 2010], IL‐1β stimulation led to evident phosphorylation of CREB in FLS from AA rats, NOR showed notable inhibition of it. On the other hand, CREB is a phosphorylation substrate for diverse protein kinases (PKs), such as PKA, PKC, p38 MAPK, and others.…”

Section: Discussionsupporting

confidence: 92%

Norisoboldine inhibits the production of interleukin‐6 in fibroblast‐like synoviocytes from adjuvant arthritis rats through PKC/MAPK/NF‐κB‐p65/CREB pathways

Wei

Wang

Song

et al. 2012

J of Cellular Biochemistry

View full text Add to dashboard Cite

Interleukin-6 (IL-6) is a pleiotropic cytokine secreted by macrophages and others and it has been proven to be a potential therapeutic target of RA. Norisoboldine (NOR) is the main isoquinoline alkaloid constituent in the dry roots of Lindera aggregata (Sims) Kosterm. (L. strychnifolia Vill.), which has long been used in traditional Chinese medicine for treating RA and other diseases. Our previous studies indicated that NOR was able to attenuate inflammation and joint destruction in collagen II-induced arthritis of mice. To further recognize the anti-rheumatoid potentials of NOR, the present study addressed whether and how NOR interfered with IL-6 production from fibroblast-like synoviocytes (FLS), key effector cells in the development and progression of RA. FLS, obtained from the synovial tissues of rats with adjuvant arthritis, showed incremental release of IL-6 after stimulated with IL-1β in vitro. NOR (10, 30, and 60 µM) could reduce the production of IL-6 in a concentration-dependent manner. It also down-regulated the phosphorylations of mitogen-activated protein kinases (MAPKs), protein kinase C (PKC), and transcriptional factor nuclear factor-κB (NF-κB)-p65 (ser 276) as well as cAMP response element-binding protein (CREB) in FLS. By using specific inhibitors, PKC was shown to be the upstream protein of MAPKs, and p38 MAPK was at the upstream of CREB. It was concluded that preventing IL-6 release from FLS might be an important mechanism for NOR displaying anti-RA property, and the action of NOR was relative to inhibition of PKC/MAPKs/p65/CREB pathways.

show abstract

Section: Discussionsupporting

confidence: 92%

Norisoboldine inhibits the production of interleukin‐6 in fibroblast‐like synoviocytes from adjuvant arthritis rats through PKC/MAPK/NF‐κB‐p65/CREB pathways

Wei

Wang

Song

et al. 2012

J of Cellular Biochemistry

View full text Add to dashboard Cite

show abstract

“…VIP decreased both gene expression and production of TNFα and IL‐6 in synovial tissue and FLS from RA patients (Juarranz et al, 2004). Moreover, CREB protein is also implicated in IL‐6 production from arthritic synovial cells (Ishizu et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Mapping the CRF-urocortins system in human osteoarthritic and rheumatoid synovial fibroblasts: Effect of vasoactive intestinal peptide

et al. 2011

View full text Add to dashboard Cite

In addition to the brain and pituitary gland, the corticotrophin-releasing factor (CRF) system is expressed in peripheral tissues. In this study we characterize the expression of CRF, urocortins (UCN1, UCN2, and UCN3), and their receptors (CRFR1 and CRFR2) in osteoarthritis (OA) and rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS). Moreover, we analyze the vasoactive intestinal peptide (VIP) effect on the CRF system, as well as its physiological consequences on mediators of inflammatory/destructive processes. CRF and UCNs exhibit differential pattern in OA and RA-FLS. By real-time PCR we detected more expression of CRF and UCN1 in RA, and UCN2 and UCN3 in OA, while the CRFR2 expression was similar. In RA-FLS VIP treatment resulted in a significant decrease of the proinflammatory peptides, CRF and UCN1, and a significant increase of the potential anti-inflammatory agents, UCN3 and CRFR2. Using Western blot assays, we showed that the ratio between phospho-CREB (p-CREB) and c-AMP response element-binding (CREB) is higher in OA and significantly lower in RA-FLS after VIP treatment, with consequences upon cAMP response element in CRF and UCN1 genes. Real-time PCR and EIA proved that VIP significantly inhibits cycloxygenase-2 (COX-2) and prostaglandin E2 (PGE2) in RA-FLS. In all cases, we consider significant data when P < 0.05. These data indicate a role of endogenous CRF, UCNs, and CRFR2 in the OA and RA joint microenvironment. We confirm the anti-inflammatory function of VIP, through the modulation of the expression of CRF system that impacts in a reduction of mediators with inflammatory/destructive functions, supporting its therapeutic potential in rheumatic diseases.

show abstract

“…Several papers reported that the activated cAMP/CREB signaling pathway could enhance the IL10 production in human monocytes, and IFN-gamma suppressed IL10 synergize by regulating CREB/AP-1 protein expression [10,11] . CREB is expressed at a higher level in the synovial cells of patients with RA, and it is implicated in IL6 production from synovial cells [12] . However, whether the methylation status of a single CpG site in the IL10 promoter can regulate its transcription through affecting CREB's binding to this region in RA remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Hypomethylation of proximal CpG motif of interleukin-10 promoter regulates its expression in human rheumatoid arthritis

Cong

et al. 2011

Acta Pharmacol Sin

View full text Add to dashboard Cite

Aim:The promoter of human interleukin-10 (IL10), a cytokine crucial for suppressing inflammation and regulating immune responses, contains an interspecies-conserved sequence with CpG motifs. The aim of this study was to investigate whether methylation of CpG motifs could regulate the expression of IL10 in rheumatoid arthritis (RA). Methods: Bioinformatic analysis was conducted to identify the interspecies-conserved sequence in human, macaque and mouse IL10 genes. Peripheral blood mononuclear cells (PBMCs) from 20 RA patients and 20 health controls were collected. The PBMCs from 6 patients were cultured in the presence or absence of 5-azacytidine (5 μmol/L). The mRNA and protein levels of IL10 were examined using RT-PCR and ELISA, respectively. The methylation of CpGs in the IL10 promoter was determined by pyrosequencing. Chromatin immunoprecipitation (ChIP) assays were performed to detect the cyclic AMP response element-binding protein (CREB)-DNA interactions. Results: One interspecies-conserved sequence was found within the IL10 promoter. The upstream CpGs at -408, -387, -385, and -355 bp were hypermethylated in PBMCs from both the RA patients and healthy controls. In contrast, the proximal CpG at -145 was hypomethylated to much more extent in the RA patients than in the healthy controls (P=0.016), which was correlated with higher IL10 mRNA and serum levels. In the 5-azacytidine-treated PBMCs, the CpG motifs were demethylated, and the expression levels of IL10 mRNA and protein was significantly increased. CHIP assays revealed increased phospho-CREB binding to the IL10 promoter. Conclusion: The methylation of the proximal CpGs in the IL10 promoter may regulate gene transcription in RA.

show abstract

Cyclic AMP response element-binding protein is implicated in IL-6 production from arthritic synovial cells

Cited by 5 publications

References 18 publications

Norisoboldine inhibits the production of interleukin‐6 in fibroblast‐like synoviocytes from adjuvant arthritis rats through PKC/MAPK/NF‐κB‐p65/CREB pathways

Norisoboldine inhibits the production of interleukin‐6 in fibroblast‐like synoviocytes from adjuvant arthritis rats through PKC/MAPK/NF‐κB‐p65/CREB pathways

Mapping the CRF-urocortins system in human osteoarthritic and rheumatoid synovial fibroblasts: Effect of vasoactive intestinal peptide

Hypomethylation of proximal CpG motif of interleukin-10 promoter regulates its expression in human rheumatoid arthritis

Contact Info

Product

Resources

About