Restraint stress activates STAT3 via adrenoceptor stimulation and IL-6 production in mouse liver.
Johnson-EA; O'Callaghan-JP; Miller-DB
Toxicologist 2004 Mar; 78(S-1):324
In vivo stress causes an activation of the JAK-STAT signaling pathway as evidenced by the large magnitude increases in phosphorylated STAT3 in the livers of mice subjected to restraint. Restraint can elevate IL-6 levels in the liver and this cytokine is known to instigate signaling through the JAK-STAT pathway but the role of the stress mediators, epinephrine, norepinephrine and corticosterone in this cascade is not well understood. Using a combination of focused microwave irradiation to preserve protein phosphorylation state, and phospho-specific immunoblotting, we found that the greater than 10 fold increase in liver PSTAT3tyr705 caused by 2 hrs of restraint is blocked by both alpha and beta adrenergic antagonists. Adrenergic agonists (phenylephrine 10 mg/kg or isoproterenol 10 mg/kg s.c.) which mimic the stress response in vivo also activate liver STAT3. Liver responses to both restraint stress and the adrenergic agonists were reduced in IL-6 deficient animals, suggesting that IL-6 is required for signal transduction initiated by activation of adrenoceptors. Pretreatment of IL-6 deficient mice with exogenous IL-6 (1 mg/kg i.p. 60 min before restraint) restored liver STAT3 activation in response to restraint stress. Hepatocyte growth factor and epidermal growth factor were ruled out as potential mediators of restraint stress-induced activation of STAT3 using real time PCR as only message for IL-6 was elevated. Altogether, these data suggest that restraint stress and adrenergic agonist-induced activation of liver STAT3 are dependent on IL-6 synthesis mediated by activation of adrenoceptors in liver. Stress is known to modulate the liver toxicity of numerous compounds. Stress-induced changes in JAK-STAT signaling and subsequent protein transcription will help to clarify the molecular basis of stress-induced modulation of liver toxicity.
Stress; Laboratory-animals; Animals; Animal-studies; In-vivo-studies; Liver; Hormones; Hormone-activity
The Toxicologist. Society of Toxicology 43nd Annual Meeting and ToxExpo, March 21-25, 2004, Baltimore, Maryland