title: Apoptotic cells induce Mer tyrosine kinase-dependent blockade of NF-kappaB activation in dendritic cells.
abstract: Dendritic cells (DCs) play a key role in immune homeostasis and maintenance of self-tolerance. Tolerogenic DCs can be established by an encounter with apoptotic cells (ACs) and subsequent inhibition of maturation and effector functions. The receptor(s) and signaling pathway(s) involved in AC-induced inhibition of DCs have yet to be defined. We demonstrate that pretreatment with apoptotic but not necrotic cells inhibits activation of IkappaB kinase (IKK) and downstream NF-kappaB. Notably, receptor tyrosine kinase Mer (MerTK) binding of ACs is required for mediating this effect. Monocyte-derived DCs lacking MerTK expression (MerTKKD) or treated with blocking MerTK-specific antibodies (Abs) are resistant to AC-induced inhibition and continue to activate NF-kappaB and secrete proinflammatory cytokines. Blocking MerTK activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway prevents AC-induced inhibition. These results demonstrate an essential role for MerTK-mediated regulation of the PI3K/AKT and NF-kappaB pathways in AC-induced inhibition of monocyte-derived DCs.
authors.affiliation: Department of Microbiology and Immunology, Mary Ellen Jones Bldg, Rm 804, Campus Box 7290, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC 27599-7290, USA.
authors.forename: Pradip
authors.initials: P
authors.lastname: Sen
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wallet
authors.forename: Zuoan
authors.initials: Z
authors.lastname: Yi
authors.forename: Yingsu
authors.initials: Y
authors.lastname: Huang
authors.forename: Michael
authors.initials: M
authors.lastname: Henderson
authors.forename: Clayton E
authors.initials: CE
authors.lastname: Mathews
authors.forename: H Shelton
authors.initials: HS
authors.lastname: Earp
authors.forename: Glenn
authors.initials: G
authors.lastname: Matsushima
authors.forename: Albert S
authors.initials: AS
authors.lastname: Baldwin
authors.forename: Roland M
authors.initials: RM
authors.lastname: Tisch
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D017209:Apoptosis / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000276:immunology*; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D000076202:c-Mer Tyrosine Kinase
chemical_list: D000906:Antibodies; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; C490767:Mertk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase