title: Engagement of CD14 sensitizes primary monocytes to IFN-γ to produce IL-12/23p40 and IL-23 through p38 mitogen-activated protein kinase and independent of the janus kinase/signal transducers and activators of transcription signaling.
abstract: Interferon (IFN)-γ is a potent stimulator of the IL-12 family Th1 cytokines, including IL-12/23p40 and IL-23, responsible for coordinating the innate and adaptive immune responses. Our results show that IFN-γ induced the production of IL-12/23p40 and IL-23p19 mRNA as well as IL-12p40 and IL-23 proteins in primary human monocytes isolated by positive selection through anti-CD14 microbeads. These results were confirmed by IFN-γ stimulation of CD14-activated monocytes resulting in IL-12/23p40 and IL-23 production. We investigated the signaling pathways governing the regulation of IL-23 and its subunits IL-23p40 and IL-23p19 following IFN-γ stimulation. We observed a differential regulation of IL-23p19, IL-12/23p40, and IL-23 following IFN-γ stimulation. IFN-γ-induced IL-23 and IL-12/23p40 expression was positively regulated by the p38 mitogen-activated protein kinases (MAPKs), independent of the Janus kinase (Jak)/signal transducers and activators of transcription (STAT) signaling. In contrast, IL-12 and IL-23 were negatively regulated by the Jak/STAT, phosphatidylinositol 3-kinase (PI3K), and the c-Jun-N-terminal kinase (JNK) MAPKs in IFN-γ-stimulated monocytes. Overall, our results suggest for the first time a differential positive regulation of IL-12p40 and IL-23 by p38 MAPKs independent of the Jak/STAT pathways and negative regulation by the Jak/STAT, JNK, and PI3K pathways in CD14-activated primary human monocytes stimulated with IFN-γ.
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario K1H 8L1, Canada. mblah011@uottawa.ca
authors.forename: Maria A
authors.initials: MA
authors.lastname: Blahoianu
authors.forename: Ali A R
authors.initials: AA
authors.lastname: Rahimi
authors.forename: Niranjala
authors.initials: N
authors.lastname: Gajanayaka
authors.forename: Maya
authors.initials: M
authors.lastname: Kozlowski
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Angel
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D053762:Interleukin-12 Subunit p40 / Q000235:genetics / Q000378:metabolism*; D053759:Interleukin-23 / Q000235:genetics / Q000378:metabolism*; D053760:Interleukin-23 Subunit p19 / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017471:Receptors, Interferon / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000096743:Interferon gamma Receptor
chemical_list: D007371:Interferon-gamma; D053762:Interleukin-12 Subunit p40; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D048031:JNK Mitogen-Activated Protein Kinases; D053612:Janus Kinases; D018950:Lipopolysaccharide Receptors; D019869:Phosphatidylinositol 3-Kinases; D017471:Receptors, Interferon; D050791:STAT Transcription Factors; D051197:Toll-Like Receptor 4; D048051:p38 Mitogen-Activated Protein Kinases; D000096743:Interferon gamma Receptor; C495345:TLR4 protein, human