Inhibition of interleukin-6-activated janus kinases/signal transducers and activators of transcription but not mitogen-activated protein kinase signaling in liver of endotoxin-treated rats.
OBJECTIVE
Endotoxin-induced cytokines, such as interleukin-6, mediate systemic inflammatory responses through multiple cellular signaling pathways. Interleukin-6 is also responsible for the synthesis of acute phase proteins. Recent studies have shown that endotoxin can inhibit signal transducers and activators of transcription (STAT)-3 tyrosine phosphorylation in cultured cells, suggesting that this effect may limit the synthesis of acute phase proteins. The purpose of this study was to examine the effects of endotoxin on interleukin-6 activation of STATs and mitogen-activated protein (MAP) kinase pathways in rat liver in vivo.


METHODS
Controlled laboratory study.


METHODS
Medical school laboratory.


METHODS
Specific pathogen-free male Sprague Dawley rats.


METHODS
Under anesthesia, interleukin-6 was injected into the portal vein of rats 4 hrs after the bolus intravenous administration of endotoxin (1 mg/kg) or saline. The effects of interleukin-6 on key intermediates in early steps of the interleukin-6 signaling pathway, including janus kinase-1, gp 130, the interleukin-6 receptor, STAT1, and STAT3, were examined in both saline and endotoxin-treated rats.


RESULTS
In endotoxin-treated rats, there was significant inhibition of interleukin-6 activation of janus kinase-1, gp 130, the interleukin-6 receptor, STAT1, and STAT3. These signaling changes were associated with decreased tissue abundance of interleukin-6 receptors and STAT3. In contrast to its effects on the janus kinase/STAT pathways, interleukin-6 activation of MAP kinases (extracellular signal-regulated kinase-1, extracellular signal-regulated kinase-2, and p38) was unaffected by endotoxin.


CONCLUSIONS
The pathway-specific inhibition of interleukin-6 signaling responses in the liver may be an important determinant of the pathophysiologic consequences of endotoxin exposure.
Ling
Pei-Ra
PR
Nutrition/Infection Laboratory, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Smith
Robert J
RJ
Mueller
Claudia
C
Mao
Yilei
Y
Bistrian
Bruce R
BR
D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D004731:Endotoxins / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D015850:Interleukin-6 / Q000502:physiology*; D053613:Janus Kinase 1; D008099:Liver / Q000378:metabolism; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009025:Morpholines / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects*; D013047:Specific Pathogen-Free Organisms; D015534:Trans-Activators / Q000378:metabolism
D004268:DNA-Binding Proteins; D004731:Endotoxins; D015850:Interleukin-6; D009025:Morpholines; D019947:Receptors, Interleukin-6; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494081:Stat1 protein, rat; C494088:Stat3 protein, rat; D015534:Trans-Activators; C005759:2-phenyl-5,5-dimethyltetrahydro-1,4-oxazine; D011505:Protein-Tyrosine Kinases; C507906:Jak1 protein, rat; D053613:Janus Kinase 1; D020928:Mitogen-Activated Protein Kinases