Repression of SMAD3 by STAT3 and c-SKI is essential for conventional dendritic cell differentiation
Jeong-Hwan Yoon1, 2, Eunjin Bae1, 2, Katsuko Sudo3, Seok Hee Park4, Michael Weinstein5, Sungmi Park6, Jae-Han Jeon1, 6, Susumu Nakae7, In-Kyu Lee1, 6, Ji Hyeon Ju8, Isao Matsumoto9, Takayuki Sumida9, Masahiko Kuroda2, Keiji Miyazawa10, Mitsuyasu Kato11, Mizuko Mamura1, 2, 12
1Biomedical Research Institute, Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea, Republic of (South), 2Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan, 3Animal Research Center, Tokyo Medical University, Tokyo, Japan, 4Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea, Republic of (South), 5Department of Molecular Genetics, The Ohio University, Columbus, OH, Columbus, United States, 6Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Medical Center, Daegu, Korea, Republic of (South), 7Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan, 8Department of Rheumatology, Catholic University of Korea, Seoul St. Mary Hospital, Seoul, Korea, Republic of (South), 9Department of Internal Medicine, University of Tsukuba, Tsukuba, Japan, 10Departments of Biochemistry, University of Yamanashi, Yamanashi, Japan, 11Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences and Faculty of Medicine, University of Tsukuba, Tsukuba, Japan, 12Physician, Student and Researcher Support Center, Tokyo Medical University, Tokyo, Japan
Transforming growth factor-β (TGF-β) plays pleiotropic regulatory roles in dendritic cell (DC) development. However, the signalling mechanisms how TGF-β differentially regulates the development of DC subsets remain largely unknown. Here, we show that selective downregulation of one of the TGF-β receptor-regulated SMADs, SMAD3 by STAT3 and c-SKI is essential for conventional or classical DC (cDC) differentiation. We found that the expression of SMAD3 was decreased, whereas SMAD2 remained expressed in cDCs. SMAD3 deficiency facilitated cDC differentiation with the increase of CD135+CD115+Lin- cDC precursor cells and cDCs along with the decrease of CD117+CD135+CD115+Lin- macrophage-DC precursor (MDP) cells in bone marrow, whereas SMAD2 deficiency did not affect DC differentiation. We found that SMAD3 transcribed by SMAD2 and SMAD3 repressed the genes essential for cDC differentiation such as Flt3, IRF4 and STAT3 in the progenitor cells. Furthermore, STAT3 repressed SMAD3 for Flt3L or GM-CSF/IL-4-induced cDC differentiation in synergy with c-SKI, a negative regulator of SMAD-mediated TGF-β signalling. Our data reveal the cross-regulation between SMAD3 and STAT3 specific for cDC differentiation from MDP.