Abstract
CREB binding protein (CBP), a transcriptional coactivator and acetyltransferase, is involved in the pathogenesis of inflammation-related diseases. High mobility group box-1 protein (HMGB1) is a critical mediator of lethal sepsis, which has prompted investigation for the development of new treatment for inflammation. Here, we report that the potent and selective inhibition of CBP bromodomain by SGC-CBP30 blocks HMGB1-mediated inflammatory responses in vitro and in vivo. Our data suggest that CBP bromodomain inhibition suppresses LPS-induced expression and release of HMGB1, when the inhibitor was given 8 h post LPS stimulation; moreover, CBP bromodomain inhibition attenuated pro-inflammatory activity of HMGB1. Furthermore, our findings provide evidence that SGC-CBP30 down-regulated rhHMGB1-induced activation of MAPKs and NF-κB signaling by triggering the reactivation of protein phosphatase 2A (PP2A) and the stabilization of MAPK phosphatase 1 (MKP-1). Collectively, these results suggest that CBP bromodomain could serve as a candidate therapeutic target for the treatment of lethal sepsis via inhibiting LPS-induced expression and release of HMGB1 and suppressing the pro-inflammatory activity of HMGB1.
Highlights
CREB binding protein (CBP, known as CREBBP or KAT3A) was identified as a factor binding to the cAMP response element-binding protein (CREB) [1]
We demonstrated that inhibition of CBP bromodomain at 8 h following the onset of sepsis by the selective and potent inhibitor SGC-CBP30 significantly increased the survival rate of mice with severe sepsis, at least in part, through a mechanism that involves expression, active release, and the pro-inflammatory activity of High mobility group box1 protein (HMGB1)
Previous studies have shown that administration of HMGB1 to experimental mice caused lethal organ damage, while passive immunization with neutralizing anti-HMGB1 antibodies before or after endotoxin exposure reversed the lethality of established sepsis, and decreased organ injury in mice subjected to severe sepsis [44]
Summary
CREB binding protein (CBP, known as CREBBP or KAT3A) was identified as a factor binding to the cAMP response element-binding protein (CREB) [1]. The bromodomain of CBP is closely related to its biological functions, including the identification of the lysine residues to be acetylated [2]. Therapeutic targeting of bromodomains has been recognized as a valuable potential therapy for human malignant inflammatory diseases [5,6,7]. The reasons for the failure are probably related more to the difficulty in designing clinical trials to inhibit the classic pro-inflammatory cytokines in proper, avoiding damage from the innate immune response. Another non-negligible problem is that patients often come to medical attention relatively late in the disease, and blocking these early cytokines may be too late
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