Fibroblasts from type 1 diabetics exhibit enhanced Ca(2+) mobilization after TNF or fat exposure.
The effects of cytokine and fatty acid treatment on signal transduction in dermal fibroblasts from type 1 diabetics and matched controls were compared. Chronic exposure to TNF, accentuated Ca(2+) mobilization in response to bradykinin (BK) in cells from both controls and diabetics; responses were three-fold greater in cells from diabetics than in controls. Similarly, with chronic exposure to IL-1β, BK-induced Ca(2+) mobilization was accentuated in cells from type 1 diabetics compared to the controls. Pretreatment with the protein synthesis inhibitor cycloheximide or the protein kinase C inhibitor calphostin C prior to the addition of TNF completely abrogated the TNF-induced increment in peak bradykinin response. Ca(2+) transients induced by depleting endoplasmic reticulum (ER) Ca(2+) with thapsigargin were also greater in TNF treated fibroblasts than in untreated cells, with greater increases in cells from diabetics. Exposing fibroblasts for 48 hours to 2 mM oleate also increased both the peak bradykinin response and the TNF-induced increment in peak response, which were significantly greater in diabetics than controls. These data indicate that cells from diabetic patients acquire elevated ER Ca(2+) stores in response to both cytokines and free fatty acids,and thus exhibit greater sensitivity to environmental inflammatory stimuli and elevated lipids.
Obesity Research Center, Evans Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
Nicholas R
NR
Husni
Obesity Research Center, Evans Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
Albert R
AR
Jones
Obesity Research Center, Evans Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
Amber L
AL
Simmons
Obesity Research Center, Evans Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
Barbara E
BE
Corkey
D015153:Blotting, Western; D001920:Bradykinin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D020405:Dermis / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D018002:Receptors, Bradykinin / Q000378:metabolism; D035781:Siblings; D015398:Signal Transduction; D019284:Thapsigargin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D016207:Cytokines; D004791:Enzyme Inhibitors; D005230:Fatty Acids, Nonesterified; D007375:Interleukin-1; D018002:Receptors, Bradykinin; D014409:Tumor Necrosis Factor-alpha; D019284:Thapsigargin; D001920:Bradykinin; D002118:Calcium