title: Casein kinase 2-interacting protein-1, an inflammatory signaling molecule interferes with TNF reverse signaling in human model cells.
abstract: When transmembrane form of tumor necrosis factor (mTNF) interacts with its cognate receptors or agonistic antibodies signaling pathways are activated in the ligand expressing cells. This "reverse signaling" appears a fine-tuning control mechanism in the immune response. Despite a clinical relevance key molecules of TNF reverse signaling and their functions remain elusive. We examined the role of CKIP-1, an interacting partner of the N terminal fragment of mTNF in inflammation and TNF reverse signaling. We found that CKIP-1 expression was elevated upon LPS challenge in THP-1 human monocyte model cells. Overexpression of CKIP-1 triggered classical activation of THP-1 cells and transactivated the human TNF promoter when co-expressed with c-Jun in the HEK293 model system. TNF reverse signaling induced a massive translocation of CKIP-1 from the plasma membrane to intracellular compartments in THP-1 cells. Expression of the N terminal fragment of mTNF in HEK293 cells resembled the effects of TNF reverse signaling with respect to relocalization of CKIP-1. In parallel with the translocation, CKIP-1-triggered activation of THP-1 cells was antagonized by TNF reverse signaling. Similarly, the presence of the N terminal fragment of mTNF inhibited CKIP-1 mediated TNF promoter activation in HEK293 cells. Both TNF reverse signaling in THP-1 cells and expression of the N terminal fragment of mTNF in HEK293 cells were found to induce apoptosis that could be prevented by overexpression of CKIP-1. Our findings demonstrate that CKIP-1 activates pro-inflammatory pathways and interferes with TNF reverse signaling induced apoptosis in human model cells.
authors.affiliation: Center for Advanced Bioanalysis GmbH, Linz, Austria.
authors.forename: Kata
authors.initials: K
authors.lastname: Juhász
authors.forename: Agnes
authors.initials: A
authors.lastname: Zvara
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Lipp
authors.forename: Benedikt
authors.initials: B
authors.lastname: Nimmervoll
authors.forename: Alois
authors.initials: A
authors.lastname: Sonnleitner
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Balogi
authors.forename: Ernő
authors.initials: E
authors.lastname: Duda
mesh_terms: D017209:Apoptosis / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological; D057809:HEK293 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009000:Monocytes / Q000276:immunology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000235:genetics; D019076:Transgenes / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D008565:Membrane Proteins; C408877:PLEKHO1 protein, human; D014409:Tumor Necrosis Factor-alpha