title: Dendritic cell maturation and IL-12 synthesis induced by the synthetic immune-response modifier S-28463.
abstract: Dendritic cells (DC) play a prominent role in the development of T cell-immune responses to antigens and have a key influence over the differentiation of naive T cells into T helper cell type 1 (Th1) or Th2 effector cells. Consequently, there is considerable interest in pharmacological agents that might alter DC function and thereby modulate allergic inflammation. We examined the effects of the imidazoquinoline S-28463 on human monocyte-derived DC (Mo-DC) cultured in granulocyte macrophage-colony stimulating factor and interleukin (IL)-4 to determine whether this agent might be useful in augmenting Th1 immunity. We determined that S-28463 acts directly on Mo-DC, inducing their maturation and enhancing their capacity to present antigen. Importantly, S-28463 strongly induces synthesis of bioactive IL-12 p70, a key Th1-polarizing cytokine. We also examined the ability of S-28463 to modulate DC function in the context of transforming growth factor-beta (TGF-beta), a negative, immunoregulatory cytokine released from the epithelium of nonlymphoid organs. S-28463 was able to induce IL-12 synthesis even in the presence of TGF-beta, whereas lipopolysaccharide (LPS) + interferon-gamma-stimulated DC did not produce IL-12 in the presence of TGF-beta. Taken together, our findings suggest that S-28463 and LPS are exerting their effects via distinctly different pathways and indicate that S-28463 may be beneficial in polarizing immune responses toward a Th1 response.
authors.affiliation: Asthma & Allergy Research Institute and Department of Medicine, University of Western Australia, Sir Charles Gairdner Hospital, Nedlands.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Fogel
authors.forename: Julie A
authors.initials: JA
authors.lastname: Long
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Thompson
authors.forename: John W
authors.initials: JW
authors.lastname: Upham
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000634:Aminoquinolines / Q000494:pharmacology*; D017951:Antigen Presentation / Q000187:drug effects; D015703:Antigens, CD / Q000378:metabolism; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen; D002454:Cell Differentiation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism; D009000:Monocytes / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497964:CD86 protein, human; D006684:HLA-DR Antigens; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; C099445:S 28463; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D018664:Interleukin-12