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The Effect of Interleukin 6 on Mitogen Activated Protein Kinase and Suppressors of Cytokine Signalling 3 Expression in Lung Ischemia Reperfusion
H. E. Merry, A. S. McCourtie, A. S. Farivar, M. F. Delgado, M. S. Mulligan*. University of Washington, Seattle, WA,
Objectives: The mechanism for interleukin 6 modulating ischemia-reperfusion injury remains poorly characterized. In vivo exogenous IL-6 reduces endothelial disruption and neutrophil sequestration in lung ischemia-reperfusion injury. This study attempts to characterize the mechanisms by which exogenous IL-6 confers protection in lung ischemia-reperfusion injury.
Methods: For in vivo data, rats were pretreated with 150ng of IL-6 intractracheally and underwent 90 minutes of left lung ischemia and 15 minutes of reperfusion. Total protein was then harvested from whole lung homogenates and western blots were then performed. For in vitro studies cultured rat type 2 pneumocytes and pulmonary artery endothelial cells were pretreated with 1ng/ml of IL-6. Cells were then subjected to 120 minutes of hypoxia and 15 minutes of reoxygentation. The effects of exogenous IL-6 on early markers of lung ischemia reperfusion injury, including mitogen activated protein kinase activation and nuclear translocation of transcription factors were then analyzed.
Results: In vivo IL-6 was associated with reduced activation of ERK ½, p38 and JNK. SOCS 3 was increased with ischemia-reperfusion. In vitro pulmonary artery endothelial cells and type 2 pneumocytes showed a reduction in ERK ½ phosphorylation. In addition, in pulmonary artery endothelial cells there was reduction in NFkB and EGR-1 nuclear translocation and upregulation of SOCS-3.
Conclusions: Exogenous IL-6 has a role in potentiating lung ischemia reperfusion injury. Mechanistically this effect appears to be modulated through decreased MAPK activation and feedback through upregulation of the Suppressors of Cytokine Signaling 3 (SOCS3) pathway. The physiologic effects of exogenous IL-6 are currently being investigated.
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