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J Immunol. 2015 Jan 1;194(1):316-24. doi: 10.4049/jimmunol.1401013. Epub 2014 Dec 1.

Crosstalk among IL-23 and DNAX activating protein of 12 kDa-dependent pathways promotes osteoclastogenesis.

Author information

1
Department of Internal Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA 95616;
2
Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of California Davis Medical Center, Sacramento, CA 95817;
3
Discovery Research, Department of Immunology and Immunomodulatory Receptors, Merck Research Laboratories, Palo Alto, CA 94304; and.
4
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.

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.

PMID:
25452564
PMCID:
PMC4272876
DOI:
10.4049/jimmunol.1401013
[Indexed for MEDLINE]
Free PMC Article

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