Upregulated promitogenic signaling via cytokines and growth factors: potential mechanism of robust liver tissue repair in calorie-restricted rats upon toxic challenge.
Previously we reported that moderate calorie restriction or diet restriction (DR, calories reduced by 35% for 21 days) in male Sprague-Dawley rats protects from a lethal dose of thioacetamide (TA). DR rats had 70% survival compared with 10% in rats fed ad libitum (AL) because of timely and adequate compensatory liver cell division and tissue repair in the DR rats. Further investigation of the mechanisms indicate that enhanced promitogenic signaling plays a critical role in this stimulated tissue repair. Expression of stimulators of promitogenic signaling interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), hepatocyte growth factor (HGF), transforming growth factor-alpha (TGF-alpha), and epidermal growth factor receptor (EGFR) were studied during liver tissue repair after TA-induced liver injury. Plasma IL-6 was significantly higher in the DR rats, with 6-fold higher expression at 48 h after TA administration. Immunohistochemical localization revealed significantly higher expression of IL-6 in the hepatic sinusoidal endothelium of DR rats. Expression of TGF-alpha and HGF was consistently higher in the livers of DR rats from 36 to 72 h. EGFR, which serves as a receptor for TGF-alpha, was higher in DR rats before TA administration and remained higher till 48 h after TA intoxication. DR-induced 2-fold increase in hepatic iNOS activity is consistent with early cell division in DR rats after TA challenge. These data suggest that the reason behind the higher liver tissue repair after TA-induced hepatotoxicity in DR rats is timely and higher expression of the growth stimulatory cytokines and growth factors. It appears that the physiological effects of DR make the liver cells vigilant and prime the liver tissue promptly for liver regeneration through promitogenic signaling upon toxic challenge.
Apte
Udayan M
UM
Department of Toxicology, College of Pharmacy, The University of Louisiana at Monroe, 700 University Avenue, Sugar Hall 306B, Monroe, LA 71209-0495, USA.
Limaye
Pallavi B
PB
Ramaiah
Shashi K
SK
Vaidya
Vishal S
VS
Bucci
Thomas J
TJ
Warbritton
Alan
A
Mehendale
Harihara M
HM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D031204:Caloric Restriction; D002455:Cell Division / Q000187:drug effects; D016207:Cytokines / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D004815:Epidermal Growth Factor / Q000502:physiology; D006133:Growth Substances / Q000502:physiology*; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis / Q000502:physiology; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000502:physiology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology*; D008115:Liver Regeneration / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D008938:Mitosis / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D016207:Cytokines; D006133:Growth Substances; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D020928:Mitogen-Activated Protein Kinases