Regulation of insulin-like growth factor binding protein-1 expression during aging.
Insulin-like growth factor (IGF) binding protein-1 (IGFBP-1) is primarily produced in the liver during inflammation and regulates biological activities of IGF-I. Here we demonstrate that interleukin-1beta (IL-1beta) stimulates IGFBP-1 mRNA production in a dose-dependent manner in hepatocytes from Fisher 344 rats. Employment of c-Jun N-terminal kinase (JNK) inhibitor SP600125 resulted in 3-fold reduction of IGFBP-1 mRNA and protein levels, indicating that IL-1beta-induced IGFBP-1 production is mediated through JNK activation. We further show that hepatocytes from aged rats (20-22 mo), as compared to young (3-4 mo), exhibit up to 2-fold higher levels of IGFBP-1 in response to IL-1beta. IL-1beta-induced phosphorylation of JNK was also significantly higher in aged hepatocytes, and SP600125 treatment eliminated age-related differences in IGFBP-1 mRNA production. Moreover, glutathione depletion in hepatocytes from young rats potently activated JNK, as well as increased IL-1beta-induced IGFBP-1 mRNA levels, suggesting that age-related oxidative stress underlies the upregulated JNK activation and IGFBP-1 expression.
Rutkute
Kristina
K
Department of Physiology, University of Kentucky College of Medicine, A.B. Chandler Medical Center, 800 Rose St., Lexington, KY 40536, USA.
Nikolova-Karakashian
Mariana N
MN
D000375:Aging / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics* / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*
D018970:Insulin-Like Growth Factor Binding Protein 1; D053583:Interleukin-1beta; D012333:RNA, Messenger; D048031:JNK Mitogen-Activated Protein Kinases