Transcriptional suppression of interleukin-12 gene expression following phagocytosis of apoptotic cells.
Phagocytosis of apoptotic cells usually results in an anti-inflammatory state with inhibition of proinflammatory cytokines such as IL-12. How apoptotic cell-derived signals regulate IL-12 gene expression is not understood. We demonstrate that cell-cell contact with apoptotic cells is sufficient to induce profound inhibition of IL-12 production by activated macrophages. Phosphatidylserine could mimic the inhibitory effect. The inhibition does not involve autocrine or paracrine actions of IL-10 and TGF-beta. We report the identification, purification, and cloning of a novel zinc finger nuclear factor, named GC binding protein (GC-BP), that is induced following phagocytosis of apoptotic cells by macrophages or by treatment with phosphatidylserine. GC-BP selectively inhibits IL-12 p35 gene transcription by binding to its promoter in vitro and in vivo, thus decreasing IL-12 production. Blocking GC-BP by RNA interference restores IL-12 p35 transcription and IL-12 p70 synthesis. Finally, GC-BP itself undergoes functionally significant tyrosine dephosphorylation in response to apoptotic cells.
Kim
Sunjung
S
Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
Elkon
Keith B
KB
Ma
Xiaojing
X
D017209:Apoptosis; D002450:Cell Communication; D002478:Cells, Cultured; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics*; D053765:Interleukin-12 Subunit p35; D010587:Phagocytosis; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D021122:Protein Subunits / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D012097:Repressor Proteins / Q000502:physiology; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000502:physiology; D053773:Transforming Growth Factor beta1
D018664:Interleukin-12; D053765:Interleukin-12 Subunit p35; D021122:Protein Subunits; D012333:RNA, Messenger; D012097:Repressor Proteins; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C515558:Zfp668 protein, mouse; C072278:GCFC2 protein, human; C508858:IL12A protein, human; C508960:TGFB1 protein, human