期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2021798118
关键词
cytokine storm; colon cancer; HIPK2; HDAC3 phosphorylation; p65 acetylation
资金
- National Natural Science Foundation of China [81630043, 81825011, 81571617, 81961160738]
- Ministry of Science and Technology of China [2016YFD500407, 2016YFC0905902, 2016YFD0500207]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDB19030200]
- NSF
Inflammation is crucial for pathogen clearance, but excessive inflammation can lead to diseases like cancer and sepsis. The HIPK2-HDAC3-p65 module in macrophages functions to restrain excessive inflammation, potentially offering a new therapeutic mechanism for colitis-associated colorectal cancer and sepsis.
Although inflammation is critical for the clearance of pathogens, uncontrolled inflammation also contributes to the development of multiple diseases such as cancer and sepsis. Since NF-kappa B-mediated transactivation in the nucleus is pivotal downstream of various stimuli to induce inflammation, searching the nuclear-localized targets specifically regulating NF-kappa B activation will provide important therapeutic application. Here, we have identified that homeodomaininteracting protein kinase 2 (HIPK2), a nuclear serine/threonine kinase, increases its expression in inflammatory macrophages. Importantly, HIPK2 deficiency or overexpression could enhance or inhibit inflammatory responses in LPS-stimulated macrophages, respectively. HIPK2-deficient mice were more susceptible to LPSinduced endotoxemia and CLP-induced sepsis. Adoptive transfer of Hipk(2+/-) bone marrow cells (BMs) also aggravated AOM/DSS-induced colorectal cancer. Mechanistically, HIPK2 bound and phosphorylated histone deacetylase 3 (HDAC3) at serine 374 to inhibit its enzymatic activity, thus reducing the deacetylation of p65 at lysine 218 to suppress NF-kappa B activation. Notably, the HDAC3 inhibitors protected wild-type or Hipk2(-/-) BMs-reconstituted mice from LPS-induced endotoxemia. Our findings suggest that the HIPK2HDAC3-p65 module in macrophages restrains excessive inflammation, which may represent a new layer of therapeutic mechanism for colitis-associated colorectal cancer and sepsis.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据