A vitamin D analog down-regulates proinflammatory chemokine production by pancreatic islets inhibiting T cell recruitment and type 1 diabetes development.
Type 1 diabetes (T1D) is an autoimmune disease characterized by leukocyte infiltration into the pancreatic islets, and we have previously shown that treatment of adult NOD mice with a vitamin D analog arrests the progression of insulitis, blocks Th1 cell infiltration into the pancreas, and markedly reduces T1D development, suggesting inhibition of chemokine production by islet cells. In this study, we show that all TLRs are expressed by mouse and human islet cells, and their engagement by pathogen-derived ligands markedly enhances proinflammatory chemokine production. The vitamin D analog significantly down-regulates in vitro and in vivo proinflammatory chemokine production by islet cells, inhibiting T cell recruitment into the pancreatic islets and T1D development. The inhibition of islet chemokine production in vivo persists after restimulation with TLR ligands and is associated with up-regulation of IkappaBalpha transcription, an inhibitor of NF-kappaB and with arrest of NF-kappaBp65 nuclear translocation, highlighting a novel mechanism of action exerted by vitamin D receptor ligands potentially relevant for the treatment of T1D and other autoimmune diseases.
Giarratana
Nadia
N
BioXell, Milan, Italy.
Penna
Giuseppe
G
Amuchastegui
Susana
S
Mariani
Roberto
R
Daniel
Kenn C
KC
Adorini
Luciano
L
D000818:Animals; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis* / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D015536:Down-Regulation; D005455:Fluorescent Antibody Technique; D006801:Humans; D020672:I-kappa B Proteins / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*; D014807:Vitamin D / Q000031:analogs & derivatives / Q000494:pharmacology*
D018925:Chemokines; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D011948:Receptors, Antigen, T-Cell; D000072000:NF-KappaB Inhibitor alpha; D014807:Vitamin D