title: Casein Kinase 2 Interacting Protein-1 regulates M1 and M2 inflammatory macrophage polarization.
abstract: The importance of macrophage plasticity, albeit being discovered recently, has been highlighted in a broad spectrum of biological processes operative in physiological and pathological environments. Macrophage polarized activation and inactivation has profound effects on immune and inflammatory responses with several major pathways being elucidated in the past few years. However, transcriptional regulation mechanisms governing macrophage polarization is still preliminary. In this study, we identify the Casein Kinase 2 Interacting Protein 1 (CKIP-1) as a molecular toggle manipulating macrophage speciation. CKIP-1 expression was strongly induced by pro-inflammatory M1 stimuli (LPS and IFN-γ) and robustly suppressed by M2 stimuli (IL-4 and IL-13) in human and murine macrophage. Gain and loss of function studies suggest that CKIP-1 is a prerequisite for optimal LPS-induced pro-inflammatory gene activation, which exhibits its roles in a NF-κB dependent manner. Furthermore, CKIP-1 inhibits anti-inflammatory gene expression by negatively regulating JAK1-STAT6 activation in macrophages. Taken together, these data integrated CKIP-1 expression and function as a novel transcriptional regulator of macrophage polarization and identified a double feedback loop consisting of CKIP-1 and the key regulators of the M1 and M2 macrophage effectors in polarization pathway. Moreover, the inhibitory roles of CKIP-1 in LPS-mediated sepsis and TPA-mediated cutaneous provide a new target for treatments of acute inflammation.
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing, China; Bayi Children's Hospital, Army General Hospital, Beijing, China.
authors.forename: Yuhan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing, China; Department of Infectious Diseases, Chinese PLA 532 Hospital, Huangshan, Anhui, China.
authors.forename: Yiwu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing, China; 307-lvy Translational Medicine Center, Laboratory of Oncology, Chinese PLA 307 Hospital, Beijing, China.
authors.forename: Luo
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing, China; Shanghai Fengxian Central Hospital Graduate Training Base, Department of General Surgery, Fengxian Hospital Affiliated to Southern Medical University, Shanghai, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wei
authors.affiliation: Shanghai Fengxian Central Hospital Graduate Training Base, Department of General Surgery, Fengxian Hospital Affiliated to Southern Medical University, Shanghai, China. Electronic address: zhangxl2017@smu.edu.cn.
authors.forename: Xueli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing, China. Electronic address: hefc@bmi.ac.cn.
authors.forename: Fuchu
authors.initials: F
authors.lastname: He
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing, China. Electronic address: zhanglq@nic.bmi.ac.cn.
authors.forename: Lingqiang
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016764:Cell Polarity / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D018793:Interleukin-13 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D010641:Phenotype; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D018793:Interleukin-13; D015847:Interleukin-4; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D050800:STAT6 Transcription Factor; C408877:PLEKHO1 protein, human; C000620556:PLEKHO1 protein, mouse
keywords: CKIP-1; Inflammation; Lipopolysaccharide (LPS); Macrophage; NF-κB transcription factor; STAT transcription factor 6