title: Pam3CSK(4) enhanced beta cell loss and diabetogenesis: the roles of IFN-gamma and IL-17.
abstract: Toll like receptors are primary sensors of both innate and adaptive immune systems. They activate APCs and influence T-cell function in inflammatory autoimmune response. Studies have shown that TLR manipulation may lead to either tolerance or trigger autoimmunity. Using diabetogenic and subdiabetogenic multiple low doses of streptozotocin, we demonstrate here that Pam3 CYS-CK4 a TLR-2 agonist, enhances and promotes diabetes in C57BL/6 male mice following increased apoptosis of β islet cells. FACS analysis of isolated pancreatic lymph node cells revealed significant increased number of macrophages, dendritic cells, CD4(+) TNF-α(+), CD4(+) IFN-γ(+) and most significantly, CD4(+) IL-17(+) and reduced number of CD25(+)Fox p3(+) T cells after Pam3CSK4 treatment. Genetic deletion of IFN-γ prevents whereas deletion of IL-17 reduced severity of Pam3CSK4-induced enhancement of diabetes. TLR-2 agonist-enhanced diabetogenesis is also influenced by enhanced influx of antigen presenting cells and suppression of regulatory T cell activity.
authors.affiliation: Department of Microbiology and Immunology, College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates.
authors.forename: Mariam
authors.initials: M
authors.lastname: Al Shamsi
authors.forename: Allen
authors.initials: A
authors.lastname: Shahin
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Miodrag L
authors.initials: ML
authors.lastname: Lukic
authors.forename: Eric P K
authors.initials: EP
authors.lastname: Mensah-Brown
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D003921:Diabetes Mellitus, Experimental / Q000276:immunology*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology*; D055666:Lipopeptides / Q000494:pharmacology*; D008198:Lymph Nodes / Q000166:cytology; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051195:Toll-Like Receptor 2 / Q000819:agonists*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D020381:Interleukin-17; D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: Apoptosis; Autoimmunity; Proinflammatory cytokines; Subdiabetogenic dose