title: Crosstalk among IL-23 and DNAX activating protein of 12 kDa-dependent pathways promotes osteoclastogenesis.
abstract: IL-23 has been well studied in the context of T cell differentiation; however, its role in the differentiation of myeloid progenitors is less clear. In this paper, we describe a novel role of IL-23 in myeloid cell differentiation. Specifically, we have identified that in human PBMCs, IL-23 induces the expression of MDL-1, a PU.1 transcriptional target during myeloid differentiation, which orchestrates osteoclast differentiation through activation of DNAX activating protein of 12 kDa and its ITAMs. The molecular events that lead to the differentiation of human macrophages to terminally differentiated osteoclasts are dependent on spleen tyrosine kinase and phospholipase Cγ2 phosphorylation for the induction of intracellular calcium flux and the subsequent activation of master regulator osteoclast transcription factor NFATc1. IL-23-elicited osteoclastogenesis is independent of the receptor activator of NF-κB ligand pathway and uses a unique myeloid DNAX activating protein of 12 kDa-associated lectin-1(+)/DNAX activating protein of 12 kDa(+) cell subset. Our data define a novel pathway that is used by IL-23 in myeloid cells and identify a major mechanism for the stimulation of osteoclastogenesis in inflammatory arthritis.
authors.affiliation: Department of Internal Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA 95616;
authors.forename: Hyun-Seock
authors.initials: HS
authors.lastname: Shin
authors.affiliation: Department of Internal Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA 95616;
authors.forename: Ritu
authors.initials: R
authors.lastname: Sarin
authors.affiliation: Department of Internal Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA 95616;
authors.forename: Neha
authors.initials: N
authors.lastname: Dixit
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of California Davis Medical Center, Sacramento, CA 95817;
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Internal Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA 95616;
authors.forename: Eric
authors.initials: E
authors.lastname: Gershwin
authors.affiliation: Discovery Research, Department of Immunology and Immunomodulatory Receptors, Merck Research Laboratories, Palo Alto, CA 94304; and.
authors.forename: Edward P
authors.initials: EP
authors.lastname: Bowman
authors.affiliation: Department of Internal Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA 95616; Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children-Northern California, Sacramento, CA 95817 iannis@ucdavis.edu.
authors.forename: Iannis E
authors.initials: IE
authors.lastname: Adamopoulos
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D001168:Arthritis / Q000276:immunology* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D004789:Enzyme Activation; D006801:Humans; D053759:Interleukin-23 / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D037181:Lectins, C-Type / Q000096:biosynthesis; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000166:cytology* / Q000276:immunology; D008565:Membrane Proteins / Q000378:metabolism; D046912:Multiprotein Complexes / Q000096:biosynthesis; D023461:Myeloid Progenitor Cells / Q000166:cytology*; D050778:NFATC Transcription Factors / Q000096:biosynthesis / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation; D020836:Protein Structure, Quaternary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000378:metabolism; D015398:Signal Transduction; D000072377:Syk Kinase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C509771:CLEC5A protein, human; D053759:Interleukin-23; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D053245:RANK Ligand; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin; C505688:TNFSF11 protein, human; C110546:TYROBP protein, human; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D051966:Phospholipase C gamma; D002118:Calcium