Intrahepatic synthesis of tumor necrosis factor-α related to cardiac surgery is inhibited by interleukin-10 via the Janus kinase (Jak)/signal transducers and activator of transcription (STAT) pathway*

Abstract

OBJECTIVES To identify the signaling pathways involved in the anti-inflammatory shift of the cytokine balance due to hypothermia during cardiopulmonary bypass. DESIGN Experimental animal study. SETTING Department of experimental surgery of a university hospital. SUBJECTS Young pigs. INTERVENTIONS Animals underwent normothermic (37 degrees C) or hypothermic (28 degrees C) cardiopulmonary bypass (n = 6 each). Samples of liver tissue were taken before and 6 hrs after cardiopulmonary bypass. MEASUREMENTS AND MAIN RESULTS Intrahepatic expression of tumor necrosis factor-alpha, interleukin-10, inducible nitric oxide synthase, and suppressor of cytokine signaling-3 was detected by reverse transcriptase polymerase chain reaction and/or Western blotting. Concentrations of the inhibitory protein of nuclear factor-kappaB, IkappaB, and of the signal transducer and activator of transcription (STAT)-3 were measured by Western blotting. The DNA-binding activity of nuclear factor-kappaB and STAT-3 was assessed by electrophoretic mobility shift and supershift assays. Liver cell necrosis and apoptosis were assessed by histology and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay, respectively. Pigs operated on in hypothermia showed significantly higher intrahepatic concentrations of interleukin-10 and lower concentrations of tumor necrosis factor-alpha than the others. They also showed a lower percentage of hepatic cell necrosis but not of apoptosis. This anti-inflammatory reaction observed in the hypothermic group was associated with a higher expression of suppressor of cytokine signaling-3 and with increased activation of STAT-3. Activation of nuclear factor-kappaB and expression of inducible nitric oxide synthase, however, were not significantly different between both groups. CONCLUSION Our results show that hypothermia during cardiopulmonary bypass up-regulates interleukin-10 via STAT-3 activation, which in turn leads to the attenuation of tumor necrosis factor-alpha expression and to hepatic protection.

Delayed Hypothermia as Selective Head Cooling or Whole Body Cooling Does Not Protect Brain or Body in Newborn Pig Subjected to Hypoxia-Ischemia

“…There is, however, some evidence of the positive effects of HT on organ pathology in older animals (20,21). One explanation why the NT and HT groups did not differ in incidence of liver injuries in our study is that the systemic HT was mild compared with the studies discussed above.…”

Systemic and strength effects : experimental concentrations of topical menthol.

“…It has been shown to alter the nervous responses of somatosensory receptors [1-3, 6, 7, 9, 11, 12, 16-18], elicit changes in local and cellular vasoconstrictor responses [8,10,13,15,[19][20][21][22], and consequently attenuates the natural physiological inflammatory cascade [23][24][25]. Complete mechanisms for each of these responses are not clearly understood.…”

“…Studies suggest that decreased blood flow from topical cryotherapies, such as menthol, consequently blunt local inflammatory response [23,25]. Cryotherapy elicits a hepatic overexpression of interleukin-10 (IL-10), an anti-inflammatory cytokine [23]. Hypothermic tissue response increases activation of the Janus kinase signaling cascade, resulting in overproduction of I L -10 via the STAT -3 cytokine transcription pathway [23].…”

“…Studies suggest that decreased blood flow from topical cryotherapies, such as menthol, consequently blunt local inflammatory response [23,25]. Cryotherapy elicits a hepatic overexpression of interleukin-10 (IL-10), an anti-inflammatory cytokine [23].…”

“…Cryotherapy elicits a hepatic overexpression of interleukin-10 (IL-10), an anti-inflammatory cytokine [23]. Hypothermic tissue response increases activation of the Janus kinase signaling cascade, resulting in overproduction of I L -10 via the STAT -3 cytokine transcription pathway [23].…”