H89, an inhibitor of PKA and MSK, inhibits cyclic-AMP response element binding protein-mediated MAPK phosphatase-1 induction by lipopolysaccharide
- Authors
- Cho, Il Je; Woo, Na Ri; Shin, In Chul; Kim, Sang Geon
- Issue Date
- Dec-2009
- Publisher
- SPRINGER BASEL AG
- Keywords
- cAMP response element binding protein (CREB); MAPK phosphatase 1 (MKP-1); Mitogen- and stress-activated protein kinase (MSK); Protein kinase A (PKA); Toll-like receptor ligand (TLRL)
- Citation
- INFLAMMATION RESEARCH, v.58, no.12, pp.863 - 872
- Indexed
- SCIE
SCOPUS
- Journal Title
- INFLAMMATION RESEARCH
- Volume
- 58
- Number
- 12
- Start Page
- 863
- End Page
- 872
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/175773
- DOI
- 10.1007/s00011-009-0057-z
- ISSN
- 1023-3830
- Abstract
- Objective
Lipopolysaccharide (LPS) stimulates the production of inflammatory cytokines and the amplification of immune responses via MAPK pathways. MAPK phosphatases (MKPs) feedback-regulate the activities of MAPKs to prevent excessive immunological functions. H89 has been used as an inhibitor of the protein kinase A (PKA) and mitogen- and stress-activated protein kinase (MSK) pathways. In view of the potential roles of PKA and MSK for MKP-1 induction and the ability of H89 to inhibit these kinases, this study examined the effect of H89 on MKP-1 induction by LPS and the role of cyclic-AMP response element binding protein (CREB) in the MKP-1 induction.
Results
H89 treatment inhibited increases in MKP-1 protein and mRNA levels, and gene transcription by LPS in Raw264.7 cells. Immunoblot, gel-shift, and chromatin-immunoprecipitation assays showed the activation of CREB by LPS, and the ability of H89 to inhibit it, suggesting that H89’s inhibition of CREB may affect MKP-1 induction. In addition, H89 prevented the ability of LPS to induce other MKP genes (Dusp-2, 4, 8, and 16). Experiments using MAPK inhibitors showed that MAPKs are involved in CREB phosphorylation and MKP-1 induction, suggesting that CREB-mediated MKP-1 induction serves in part as a feedback-inhibitory loop of MAPKs.
Conclusion
Our results demonstrate that H89 inhibits the activation of CREB and the CREB-mediated MKP-1 induction by LPS, which may result from its inhibition of PKA and MSK.
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