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Macrophage Migration Inhibitory Factor Down‐Regulates the RANKL–RANK Signaling Pathway by Activating Lyn Tyrosine Kinase in Mouse Models
Author(s) -
Mun Se Hwan,
Oh Dongmyung,
Lee SunKyeong
Publication year - 2014
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.38723
Subject(s) - lyn , rankl , macrophage migration inhibitory factor , syk , phosphorylation , signal transduction , microbiology and biotechnology , rank ligand , cd74 , cancer research , receptor , tyrosine kinase , proto oncogene tyrosine protein kinase src , chemistry , biology , immunology , activator (genetics) , cytokine , immune system , biochemistry , mhc class i , cd8
Objective Macrophage migration inhibitory factor (MIF) is an important modulator of innate and adaptive immunity as well as local inflammatory responses. We previously reported that MIF down‐regulated osteoclastogenesis through a mechanism that requires CD74. The aim of the current study was to examine whether MIF modulates osteoclastogenesis through Lyn phosphorylation, and whether down‐regulation of RANKL‐mediated signaling requires the association of CD74, CD44, and Lyn. Methods CD74‐knockout (CD74‐KO), CD44‐KO, and Lyn‐KO mouse models were used to investigate whether Lyn requires these receptors and coreceptors. The effects of MIF on osteoclastogenesis were assessed using Western blot analysis, small interfering RNA (siRNA)–targeted down‐regulation of Lyn, Lyn‐KO mice, and real‐time imaging of Lyn molecules to surface proteins. Results MIF treatment induced Lyn expression, and MIF down‐regulated RANKL‐induced activator protein 1 (AP‐1) and the Syk/phospholipase Cγ cascade during osteoclastogenesis through activated Lyn tyrosine kinase. The results of immunoprecipitation studies revealed that MIF receptors associated with Lyn in response to MIF treatment. Studies using Lyn‐specific siRNA and Lyn‐KO mice confirmed our findings. Conclusion Our findings indicate that the tyrosine kinase Lyn is activated when MIF binds to its receptor CD74 and its coreceptor CD44 and, in turn, down‐regulates the RANKL‐mediated signaling cascade by suppressing NF‐ATc1 protein expression through down‐regulation of AP‐1 and calcium signaling components.