PMID- 29789615 OWN - NLM STAT- MEDLINE DCOM- 20191105 LR - 20191105 IS - 2041-4889 (Electronic) VI - 9 IP - 6 DP - 2018 May 22 TI - IL-37 isoform D downregulates pro-inflammatory cytokines expression in a Smad3-dependent manner. PG - 582 LID - 10.1038/s41419-018-0664-0 [doi] LID - 582 AB - IL-37 is a new member of IL-1 family and possesses five different isoforms (named as IL-37 a-e). IL-37b has been demonstrated as a physiological suppressor of immune responses. However, the function of other isoforms remains unknown. Here, we show that IL-37d possesses anti-inflammatory roles both in vitro and in vivo. Firstly, IL-37d is expressed in peripheral blood mononuclear cells (PBMCs) and umbilical cords-derived mesenchymal stem cells (UCMSCs). Secondly, IL-37d overexpression markedly inhibits IL-1beta-induced IL-6 production in A549 cells. Consistently, bone marrow-derived macrophages (BMDMs) from IL-37d transgenic mice express low levels of pro-inflammatory cytokines (such as IL-6 and TNF-alpha) following LPS stimulation, compared with those from wild-type mice. Furthermore, IL-37d transgenic mice produce less pro-inflammatory cytokines, and show much less degree of LPS-induced endotoxemia in vivo. Mechanistically, IL-37d interacts with Smad3 and promotes nuclear translocation of pSmad3. SIS3 (a specific Smad3 inhibitor) treatment completely blocks the inhibitory effects of IL-37d. Thus, our data indicate that IL-37d is a functional cytokine that negatively regulates pro-inflammatory cytokines expression in a Smad3-dependent manner. FAU - Zhao, Mingsheng AU - Zhao M AD - Department of Immunology and Key Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Basic Medical Sciences, 44 #Wenhua Xi Road, 250012, Jinan, China. FAU - Li, Yulan AU - Li Y AD - Department of Immunology and Key Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Basic Medical Sciences, 44 #Wenhua Xi Road, 250012, Jinan, China. FAU - Guo, Chun AU - Guo C AD - Department of Immunology and Key Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Basic Medical Sciences, 44 #Wenhua Xi Road, 250012, Jinan, China. FAU - Wang, Liyang AU - Wang L AD - Department of Immunology and Key Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Basic Medical Sciences, 44 #Wenhua Xi Road, 250012, Jinan, China. FAU - Chu, Hongxia AU - Chu H AD - Department of Immunology and Key Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Basic Medical Sciences, 44 #Wenhua Xi Road, 250012, Jinan, China. FAU - Zhu, Faliang AU - Zhu F AD - Department of Immunology and Key Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Basic Medical Sciences, 44 #Wenhua Xi Road, 250012, Jinan, China. FAU - Li, Yan AU - Li Y AD - Department of pathogenic biology, Shandong University School of Basic Medicine Sciences, 44# Wenhua Xi Road, 250012, Jinan, China. FAU - Wang, Xiaoyan AU - Wang X AD - Department of Immunology and Key Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Basic Medical Sciences, 44 #Wenhua Xi Road, 250012, Jinan, China. FAU - Wang, Qun AU - Wang Q AD - Department of Immunology and Key Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Basic Medical Sciences, 44 #Wenhua Xi Road, 250012, Jinan, China. FAU - Zhao, Wei AU - Zhao W AD - Department of Immunology and Key Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Basic Medical Sciences, 44 #Wenhua Xi Road, 250012, Jinan, China. FAU - Shi, Yongyu AU - Shi Y AD - Department of Immunology and Key Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Basic Medical Sciences, 44 #Wenhua Xi Road, 250012, Jinan, China. FAU - Chen, WanJun AU - Chen W AD - Mucosal Immunology Section, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), 30 Convent Drive, Bethesda, Maryland, 20892, USA. FAU - Zhang, Lining AU - Zhang L AD - Department of Immunology and Key Laboratory of Infection and Immunity of Shandong Province, Shandong University School of Basic Medical Sciences, 44 #Wenhua Xi Road, 250012, Jinan, China. zhanglining@sdu.edu.cn. LA - eng PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180522 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (Cytokines) RN - 0 (IL37 protein, human) RN - 0 (Inflammation Mediators) RN - 0 (Interleukin-1) RN - 0 (Lipopolysaccharides) RN - 0 (Protein Isoforms) RN - 0 (Receptors, Interleukin-1) RN - 0 (SIGIRR protein, human) RN - 0 (SMAD3 protein, human) RN - 0 (Smad3 Protein) SB - IM MH - A549 Cells MH - Animals MH - Cytokines/*metabolism MH - *Down-Regulation MH - Endotoxemia/pathology MH - Female MH - HEK293 Cells MH - Humans MH - Inflammation Mediators/*metabolism MH - Interleukin-1/*metabolism MH - Leukocytes, Mononuclear/metabolism MH - Lipopolysaccharides MH - Male MH - Mesenchymal Stem Cells/metabolism MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Phosphorylation MH - Protein Isoforms/metabolism MH - Receptors, Interleukin-1/metabolism MH - Smad3 Protein/*metabolism MH - Umbilical Cord PMC - PMC5964144 COIS- The authors declare that they have no conflict of interest. EDAT- 2018/05/24 06:00 MHDA- 2019/11/07 06:00 PMCR- 2018/05/22 CRDT- 2018/05/24 06:00 PHST- 2017/12/22 00:00 [received] PHST- 2018/05/03 00:00 [accepted] PHST- 2018/04/10 00:00 [revised] PHST- 2018/05/24 06:00 [entrez] PHST- 2018/05/24 06:00 [pubmed] PHST- 2019/11/07 06:00 [medline] PHST- 2018/05/22 00:00 [pmc-release] AID - 10.1038/s41419-018-0664-0 [pii] AID - 664 [pii] AID - 10.1038/s41419-018-0664-0 [doi] PST - epublish SO - Cell Death Dis. 2018 May 22;9(6):582. doi: 10.1038/s41419-018-0664-0.