THU0518 Dicam Attenuates Macrophage Differentiation via Suppression of Integrin αVβ3-Dependent Akt-Foxo3a-Irf7 Pathway
Authors: S.-W. Han, Y.-K. Jung, M.-S. Han, E.-J. Lee, H.-R. Park, G.-W. Kim, G.-B. Bae
Journal: Annals of the Rheumatic Diseases (2014)

Background DICAM, a dual Ig domain containing adhesion molecule, is involved in cell-cell adhesion through a direct interaction with αVβ3 integrin. In our previous study showing the inhibitory role in osteoclastogenesis, we found a clue that DICAM also has a suppressive role in macrophage differentiation. However, it remains still obscure the role of DICAM in macrophage differentiation and M1/M2 polarization. Objectives To investigate the role of DICAM in macrophage differentiation and M1/M2 polarization. Methods To induce differentiation into resting M0 macrophage, THP-1 cells were cultured with 100 nM PMA for 24 h, then rested for 6 days. For M1/M2 polarization, resting M0 THP-1 macrophages were treated with IFN-γ or IL-4 for 24 h. To investigate the role of DICAM during THP-1 macrophage differentiation, THP-1 cells were infected with 50 moi of control LacZ adenovirus or with DICAM adenovirus. Results The expression of DICAM was increased during PMA-induced THP-1 differentiation, and DICAM was slightly decreased by IFN-γ for M1 polarization and increased by IL-4 for M2 polarization. The overexpresion of DICAM in THP-1 cells suppressed PMA-mediated macrophage differentiation in the number of activated branched macrophage and macrophage marker expression, CD14 and CD68. However, DICAM does not affect the viability and proliferation of PMA-stimulated THP-1 macrophage. Functionally, DICAM attenuated the TNF-α secretion of differentiated THP-1 cells and their phagocytic activity as well. To investigate the molecular mechanisms for DICAM-mediated suppression of macrophage differentiation, we conducted microarray analyses, which revealed that DICAM overexpression significantly suppressed type 1 interferon system. Among interferon regulatory factors (IRFs) family, IRF7 was most significantly reduced by DICAM. DICAM also attenuated Akt activation and increased a nuclear translocation of FoxO3a that is known to be a critical negative regulator of IRF7. Consistently, DICAM also decreased total integrin β3 level and integrin-linked kinase (ILK) phosphorylation, the major adaptor molecule of integrin β3. Based on the fact that type 1 interferon is important in M1 macrophage polarization, we investigated the role of DICAM in M1/M2 polarization of macrophage. Overexpression of DICAM induced downregulation of M1-associated genes such as IL-12b p40, IL12 p19, TNFa, IL-6, and IL-1b but did not affect M2 genes, Arg1 and Fizz1. In addition, DICAM increased IL-10, but decreased TNFa and INF-β. Conclusions DICAM potently reduces differentiation and function of THP-1 macrophage and skews a THP-1 polarization into M2-like macrophage via suppression of integrin αVβ3-dependent Akt-FoxO3a-IRF7 pathway. References 1. Han SW, Jung YK, Lee EJ, Park HR, Kim GW, Jeong JH, et al. DICAM inhibits angiogenesis via suppression of AKT and p38 MAP kinase signalling. Cardiovasc Res 2013;98(1):73-82. 2. Jung YK, Han SW, Kim GW, Jeong JH, Kim HJ, Choi JY. DICAM inhibits osteoclast differentiation through attenuation of the integrin alphaVbeta3 pathway. J Bone Miner Res 2012;27(9):2024-34. 3. Jung YK, Jin JS, Jeong JH, Kim HN, Park NR, Choi JY. DICAM, a novel dual immunoglobulin domain containing cell adhesion molecule interacts with alphavbeta3 integrin. J Cell Physiol 2008;216(3):603-14. Acknowledgements This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government (2011-0007402, 2013-R1A2A2A01069204). Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.1478