title: Programmed death-1 receptor negatively regulates LPS-mediated IL-12 production and differentiation of murine macrophage RAW264.7 cells.
abstract: While programmed death-1 (PD-1), a co-inhibitory member of CD28 immunoglobulin superfamily plays negative roles in effector functions of T cells and B cells, little is known about the function of PD-1 expressed on innate immune cells. In this study, we demonstrate that IL-12 production was greatly suppressed in LPS-stimulated RAW264.7 cells upon PD-1 engagement with B7-H1.Fc fusion protein, and was restored in the presence of antagonistic anti-PD-1 mAb. PD-1-mediated suppression of IL-12 production in LPS-stimulated RAW264.7 cells was mediated by inhibition of Janus N-terminal-linked kinase (JNK) signaling pathway, and to a lesser extent, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway through the recruitment of SHP-2 to PD-1 cytoplasmic tail. B7-H1.Fc-mediated PD-1 engagement also downregulates the expression of co-stimulatory molecules such as CD80, CD86, MHC class I and II proteins in LPS-stimulated RAW264.7 cells. Furthermore, the endocytic activity is enhanced but the allostimulatory capacity is suppressed in LPS-treated RAW264.7 cells upon PD-1 engagement. Taken together, our results reveal a novel function of macrophage PD-1 in the negative regulation of IL-12 synthesis and differentiation into dendritic cell-like cells.
authors.affiliation: Department of Microbiology, Advanced Research Center for Multiple Myeloma, Inje University College of Medicine, Busan 614-735, Republic of Korea.
authors.forename: Hae-Yun
authors.initials: HY
authors.lastname: Cho
authors.forename: Eun-Kyoung
authors.initials: EK
authors.lastname: Choi
authors.forename: Soo-Woon
authors.initials: SW
authors.lastname: Lee
authors.forename: Keun-Ok
authors.initials: KO
authors.lastname: Jung
authors.forename: Su-Kil
authors.initials: SK
authors.lastname: Seo
authors.forename: Il-Whan
authors.initials: IW
authors.lastname: Choi
authors.forename: Sae-Gwang
authors.initials: SG
authors.lastname: Park
authors.forename: Inhak
authors.initials: I
authors.lastname: Choi
authors.forename: Soo-Woong
authors.initials: SW
authors.lastname: Lee
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking; D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics; D018122:B7-1 Antigen / Q000378:metabolism / Q000494:pharmacology; D060890:B7-H1 Antigen; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D015536:Down-Regulation; D004705:Endocytosis / Q000187:drug effects; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D007959:Lymphocyte Culture Test, Mixed; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology
chemical_list: D019138:Antibodies, Blocking; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; D018664:Interleukin-12; D048670:MAP Kinase Kinase 4