Phosphorylated Hsp27 prevents LPS-induced excessive inflammation in THP-1 cells via suppressing ROS-mediated upregulation of CBP.

ABSTRACT

Heat shock protein 27 (Hsp27) is a member of the small heat shock protein family expressed at high levels to protect cells against heat shock and other conditions of stress. Hsp27 has been indicated in the regulation of inflammation signaling pathway, and Hsp27 phosphorylation is vital for efficient control of host-defense response in early stages of lipopolysaccharide (LPS)-stimulated inflammation. The notion that CREB-binding protein (CBP) is involved in the regulation of two major transcription factors, nuclear factor-κB (NF-κB) and AP-1, suggests that CBP, as a coactivator protein, may also play an important role in the cellular response to inflammation. Here, we explored the mechanism underlying the regulatory relationships between Hsp27 and CBP in THP-1 cells, and found that phosphorylated Hsp27 was critical to the protein level of CBP. Furthermore, in exploring the signaling mechanisms underlying its action, we found that p38MAPK-MK2-Hsp27 regulated NF-κB via CBP, which acted as a multi-protein complex assembly scaffold. Finally, we demonstrated that phosphorylated Hsp27 reduced reactive oxygen species accumulation thereby significantly repressed LPS-induced excessive increase of CBP. Taken together, our data demonstrated that Hsp27, in its phosphorylation state, plays a critical role in controlling LPS-induced inflammatory response by modulating CBP.