title: Suppression of IL-12 production by soluble CD40 ligand: evidence for involvement of the p44/42 mitogen-activated protein kinase pathway.
abstract: IL-12 is a key cytokine in skewing immune responses toward Th1-like reactions. Human monocytes/macrophages produce high amounts of bioactive IL-12 when a priming signal (IFN-gamma or GM-CSF) precedes a second signal (e.g., LPS). We and others have previously shown that preincubation with LPS before this stimulation procedure can efficiently and selectively suppress the production of IL-12 by human monocytes. In this study, we show that an almost complete suppression of IL-12 production can also be observed after preincubation of monocytes with costimulatory cell surface molecules that bind to members of the TNFR superfamily (CD40 ligand, TNF-related activation-induced cytokine (TRANCE)). The suppression of IL-12 was observable on the mRNA and protein levels and was not due to endogenous production of known IL-12 antagonists (i.e., IL-10, IL-4, and PGE(2)), to an increased number of cells undergoing apoptosis, nor to down-regulation of the IFN-gamma or CD40 receptor. Cell surface expression of the costimulatory molecules CD80 and CD86 was not reduced by the preincubation procedure, and only a moderate reduction of IL-6 production was observed. Several studies have identified signal transduction pathways that are activated by CD40 signaling, including activation of mitogen-activated protein kinases. The presence of the extracellular signal-related kinase-specific mitogen-activated protein kinase kinase 1/2-specific inhibitors PD98059 and U0126 abrogated suppression induced by sCD40 ligand or other second signals. This indicates that activation of extracellular signal-regulated kinase 1/2 contributes to the underlying mechanism of IL-12 suppression. This mechanism may be relevant in other inflammatory responses and may help to develop therapeutic strategies in Th1-mediated diseases.
authors.affiliation: Department of Dermatology and Allergology, Hannover Medical University, Hannover, Germany. miriamwittman@web.de
authors.forename: Miriam
authors.initials: M
authors.lastname: Wittmann
authors.forename: Petra
authors.initials: P
authors.lastname: Kienlin
authors.forename: Susanne
authors.initials: S
authors.lastname: Mommert
authors.forename: Alexander
authors.initials: A
authors.lastname: Kapp
authors.forename: Thomas
authors.initials: T
authors.lastname: Werfel
mesh_terms: D017209:Apoptosis / Q000276:immunology; D023201:CD40 Ligand / Q000502:physiology*; D002478:Cells, Cultured; D015232:Dinoprostone / Q000502:physiology; D015536:Down-Regulation / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D016753:Interleukin-10 / Q000502:physiology; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D015847:Interleukin-4 / Q000502:physiology; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D009000:Monocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D012995:Solubility
chemical_list: D004791:Enzyme Inhibitors; D005419:Flavonoids; D008024:Ligands; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D016753:Interleukin-10; D023201:CD40 Ligand; D018664:Interleukin-12; D015847:Interleukin-4; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D015232:Dinoprostone; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one