Glucocorticoids reduce pro-inflammatory cytokines and tissue factor in vitro and improve function of transplanted human islets in vivo.
Factors that upregulate the inflammatory status of islets probably contribute to detrimental processes leading to islet loss and impaired post-transplant function. Glucocorticoids have the potential to counteract inflammation and thus improve islet quality and function. However, glucocorticoids have diabetogenic properties and are known to hamper islet function in vivo. We examined the effect of glucocorticoids on human islets in vitro and in vivo after 48 h of exposure to different concentrations of methylprednisolone. Protein and/or mRNA levels of insulin, interleukin (IL)-8, macrophage chemoattractant protein (MCP)-1, tissue factor (TF), and IL-10 were assessed by enzyme immunosorbent assay and real time quantitative reverse transcription-polymerase chain reaction. Viability was assessed with fluorescein diacetate-propidium iodide staining, adenosine triphosphate (ATP) content and caspase activity. Six-hundred islet equivalents (IEQ) were transplanted to severe combined immunodeficiency disease mice and graft function assessed by glucose measurements and intraperitoneal glucose tolerance tests. Glucocorticoids reduce mRNA and protein levels of TF, MCP-1 and IL-8, and enhance ATP content. Insulin secretion was initially inhibited; however, after 7 days in culture, it was superior to controls. Islets exposed to methylprednisolone cured diabetic mice more effectively than control islets. In conclusion, glucocorticoids have potent anti-inflammatory properties on human islets without permanent effects on insulin metabolism. Brief glucocorticoid exposure improves function of transplanted human islets in vivo.
Lund
Tormod
T
Surgical Clinic, Section for Transplantation, Rikshospitalet University Hospital, Oslo, Norway. tormod.lund@rikshospitalet.no
Fosby
Bjarte
B
Korsgren
Olle
O
Scholz
Hanne
H
Foss
Aksel
A
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000601:surgery; D005938:Glucocorticoids / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D006801:Humans; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D016381:Islets of Langerhans Transplantation; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology*; D051379:Mice; D016513:Mice, SCID; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013925:Thromboplastin / Q000378:metabolism*
D018932:Chemokine CCL2; D016207:Cytokines; D005938:Glucocorticoids; D018836:Inflammation Mediators; D007328:Insulin; D013925:Thromboplastin; D005947:Glucose; D008775:Methylprednisolone