Expression and regulation of chemokines in murine and human type 1 diabetes.
More than one-half of the ~50 human chemokines have been associated with or implicated in the pathogenesis of type 1 diabetes, yet their actual expression patterns in the islet environment of type 1 diabetic patients remain, at present, poorly defined. Here, we have integrated a human islet culture system, murine models of virus-induced and spontaneous type 1 diabetes, and the histopathological examination of pancreata from diabetic organ donors with the goal of providing a foundation for the informed selection of potential therapeutic targets within the chemokine/receptor family. Chemokine (C-C motif) ligand (CCL) 5 (CCL5), CCL8, CCL22, chemokine (C-X-C motif) ligand (CXCL) 9 (CXCL9), CXCL10, and chemokine (C-X3-C motif) ligand (CX3CL) 1 (CX3CL1) were the major chemokines transcribed (in an inducible nitric oxide synthase-dependent but not nuclear factor-κB-dependent fashion) and translated by human islet cells in response to in vitro inflammatory stimuli. CXCL10 was identified as the dominant chemokine expressed in vivo in the islet environment of prediabetic animals and type 1 diabetic patients, whereas CCL5, CCL8, CXCL9, and CX3CL1 proteins were present at lower levels in the islets of both species. Of importance, additional expression of the same chemokines in human acinar tissues emphasizes an underappreciated involvement of the exocrine pancreas in the natural course of type 1 diabetes that will require consideration for additional type 1 diabetes pathogenesis and immune intervention studies.
Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado, USA.
Suparna A
SA
Sarkar
Catherine E
CE
Lee
Francisco
F
Victorino
Tom T
TT
Nguyen
Jay A
JA
Walters
Adam
A
Burrack
Jens
J
Eberlein
Steven K
SK
Hildemann
Dirk
D
Homann
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D018925:Chemokines / Q000235:genetics / Q000502:physiology*; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000276:immunology*; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D007515:Islets of Langerhans / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016328:NF-kappa B / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D018925:Chemokines; D053583:Interleukin-1beta; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha