title: Cytokine production by mouse myeloid dendritic cells in relation to differentiation and terminal maturation induced by lipopolysaccharide or CD40 ligation.
abstract: Although it is known that dendritic cells (DCs) produce cytokines, there is little information about how cytokine synthesis is regulated during DC development. A range of cytokine mRNA/proteins was analyzed in immature (CD86-) or mature (CD86+) murine bone marrow (BM)- derived DCs. Highly purified, flow-sorted, immature DCs exhibited higher amounts of interleukin-1alpha (IL-1alpha), IL-1beta, tumor necrosis factor-alpha (TNF-alpha), transforming growth factor beta1 (TGF-beta1), and macrophage migration inhibitory factor (MIF) mRNA/protein than mature DCs. After differentiation, DC up-regulated the levels of IL-6 and IL-15 mRNA/protein and synthesized de novo mRNA/protein for IL-12p35, IL-12p40, and IL-18. Although immature BM-derived DCs did not stimulate naive allogeneic T cells, mature DCs elicited a mixed population of T helper (Th) 1 (mainly) and Th2 cells in 3d-mixed leukocyte reactions. CD86+ BM DCs switched to different cytokine patterns according to whether they were terminally differentiated by lipopolysaccharide (LPS) or CD40 ligation. Although both stimuli increased IL-6, IL-12p40, IL-15, and TNF-alpha mRNA/protein levels, only LPS up-regulated transcription of IL-1alpha, IL-1beta, IL-12p35, and MIF genes. Although LPS and CD40 cross-linking increased the T-cell allostimulatory function of BM DCs, only LPS stimulation shifted the balance of naive Th differentiation to Th1 cells, a mechanism dependent on the up-regulation of IL-12p35 and not of IL-23. These results demonstrate that, depending on the stimuli used to terminally mature BM DCs, DCs synthesize a different pattern of cytokines and exhibit distinct Th cell-driving potential.
authors.affiliation: Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, PA 15213, USA. morelli@imap.pitt.edu
authors.forename: A E
authors.initials: AE
authors.lastname: Morelli
authors.forename: A F
authors.initials: AF
authors.lastname: Zahorchak
authors.forename: A T
authors.initials: AT
authors.lastname: Larregina
authors.forename: B L
authors.initials: BL
authors.lastname: Colvin
authors.forename: A J
authors.initials: AJ
authors.lastname: Logar
authors.forename: T
authors.initials: T
authors.lastname: Takayama
authors.forename: L D
authors.initials: LD
authors.lastname: Falo
authors.forename: A W
authors.initials: AW
authors.lastname: Thomson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000096:biosynthesis; D051940:B7-2 Antigen; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism*; D004705:Endocytosis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D016130:Immunophenotyping; D018664:Interleukin-12 / Q000502:physiology; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D007959:Lymphocyte Culture Test, Mixed; D008263:Macrophage Migration-Inhibitory Factors / Q000096:biosynthesis / Q000235:genetics; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000096:biosynthesis; D013047:Specific Pathogen-Free Organisms; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D051940:B7-2 Antigen; D019013:CD40 Antigens; C497965:Cd86 protein, mouse; D016207:Cytokines; C508841:Il23a protein, mouse; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D008070:Lipopolysaccharides; D008263:Macrophage Migration-Inhibitory Factors; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12