title: Zinc finger protein 64 promotes Toll-like receptor-triggered proinflammatory and type I interferon production in macrophages by enhancing p65 subunit activation.
abstract: The molecular mechanisms that fine-tune the Toll-like receptor (TLR)-triggered innate immune response need further investigation. As an important transcription factor, zinc finger proteins (ZFPs) play important roles in many cell functions, including development, differentiation, tumorigenesis, and functions of the immune system. However, the role of ZFP members in the innate immune responses remains unclear. Here we showed that the expression of C2H2-type ZFP, ZFP64, was significantly up-regulated in macrophages upon stimulation with TLR ligands, including LPS, CpG oligodeoxynucleotides, or poly(I:C). ZFP64 overexpression promoted TLR-triggered TNF-α, IL-6, and IFN-β production in macrophages. Coincidently, knockdown of ZFP64 expression significantly inhibited the production of the above cytokines. However, activation of MAPK and IRF3 was not responsible for the ZFP64-mediated promotion of cytokine production. Interestingly, ZFP64 significantly up-regulated TLR-induced NF-κB activation. ZFP64 could bind to the promoter of the TNF-α, IL-6, and IFN-β genes in macrophages only after TLR ligation. Furthermore, ZFP64 associated with the NF-κB p65 subunit upon LPS stimulation, and TLR-ligated macrophages showed a lower level of p65 recruitment to the TNF-α, IL-6, and IFN-β gene promoter in the absence of ZFP64. The data identify ZFP64 as a downstream positive regulator of TLR-initiated innate immune responses by associating with the NF-κB p65 subunit, enhancing p65 recruitment to the target gene promoters and increasing p65 activation and, thus, leading to the promotion of TLR-triggered proinflammatory cytokine and type I interferon production. Our findings add mechanistic insight into the efficient activation of the TLR innate response against invading pathogens.
authors.affiliation: National Key Laboratory of Medical Molecular Biology and Department of Immunology, Chinese Academy of Medical Sciences, Beijing 100005, China.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Wang
authors.forename: Xingguang
authors.initials: X
authors.lastname: Liu
authors.forename: Yin
authors.initials: Y
authors.lastname: Liu
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Yao
authors.forename: Bo
authors.initials: B
authors.lastname: Huang
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007369:Interferon Inducers / Q000494:pharmacology; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000096:biosynthesis* / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D011070:Poly I-C / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D051193:Toll-Like Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D004268:DNA-Binding Proteins; D007369:Interferon Inducers; D050838:Interferon Regulatory Factor-3; D015850:Interleukin-6; C494233:Irf3 protein, mouse; D008070:Lipopolysaccharides; D009838:Oligodeoxyribonucleotides; C498144:Rela protein, mouse; D051193:Toll-Like Receptors; D051996:Transcription Factor RelA; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C524088:ZFP64 protein, human; D016899:Interferon-beta; D020929:Mitogen-Activated Protein Kinase Kinases; D011070:Poly I-C
keywords: Inflammation; Innate Immunity; Macrophages; NF-κB (NF-κB); Toll-like Receptors (TLR); ZFP64; p65