title: Multiple mechanisms involved in diabetes protection by lipopolysaccharide in non-obese diabetic mice.
abstract: Toll-like receptor 4 (TLR4) activation has been proposed to be important for islet cell inflammation and eventually β cell loss in the course of type 1 diabetes (T1D) development. However, according to the "hygiene hypothesis", bacterial endotoxin lipopolysaccharide (LPS), an agonist on TLR4, inhibits T1D progression. Here we investigated possible mechanisms for the protective effect of LPS on T1D development in non-obese diabetic (NOD) mice. We found that LPS administration to NOD mice during the prediabetic state neither prevented nor reversed insulitis, but delayed the onset and decreased the incidence of diabetes, and that a multiple-injection protocol is more effective than a single LPS intervention. Further, LPS administration suppressed spleen T lymphocyte proliferation, increased the generation of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs), reduced the synthesis of strong Th1 proinflammatory cytokines, and downregulated TLR4 and its downstream MyD88-dependent signaling pathway. Most importantly, multiple injections of LPS induced a potential tolerogenic dendritic cell (DC) subset with low TLR4 expression without influencing the DC phenotype. Explanting DCs from repeated LPS-treated NOD mice into NOD/SCID diabetic mice conferred sustained protective effects against the progression of diabetes in the recipients. Overall, these results suggest that multiple mechanisms are involved in the protective effects of LPS against the development of diabetes in NOD diabetic mice. These include Treg induction, down-regulation of TLR4 and its downstream MyD88-dependent signaling pathway, and the emergence of a potential tolerogenic DC subset.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Pharmacology, College of Medicine, Wuhan University of Science and Technology, Wuhan, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Cao
authors.affiliation: Section of Neurobiology, Torrey Pines Institute for Molecular Studies, Port Saint Lucie, FL, USA.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Guoxiao
authors.initials: G
authors.lastname: Yin
authors.affiliation: Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Xia
authors.affiliation: Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jingli
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: xiangming@mails.tjmu.edu.cn.
authors.forename: Ming
authors.initials: M
authors.lastname: Xiang
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000517:prevention & control*; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control; D015536:Down-Regulation; D005260:Female; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D007376:Interleukin-2 / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D016688:Mice, Inbred NOD; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000097:blood
chemical_list: D007376:Interleukin-2; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D007371:Interferon-gamma
keywords: Dendritic cells; Non-obese diabetic mice; Regulatory T cells; Toll-like receptor 4; Type 1 diabetes