Preconditioning-induced protection from oxidative injury is mediated by leukemia inhibitory factor receptor (LIFR) and its ligands in the retina.
Preconditioning with moderate oxidative stress (e.g., moderate bright light or mild hypoxia) can induce changes in retinal tissue that protect photoreceptors from a subsequent dose of lethal oxidative stress. The mechanism underlying this induced protection is likely a general mechanism of endogenous protection which has been demonstrated in heart and brain using ischemia and reperfusion. While multiple factors like bFGF, CNTF, LIF and BDNF have been hypothesized to play a role in preconditioning-induced endogenous neuroprotection, it has not yet been demonstrated which factors or receptors are playing an essential role. Using quantitative PCR techniques we provide evidence that in the retina, LIFR activating cytokines leukemia inhibitory factor (LIF), cardiotrophin-1 (CT-1) and cardiotrophin like cytokine (CLC) are strongly upregulated in response to preconditioning with bright cyclic light leading to robust activation of signal transducer and activator of transcription-3 (STAT3) in a time-dependent manner. Further, we found that blocking LIFR activation during preconditioning using a LIFR antagonist (LIF05) attenuated the induced STAT3 activation and also resulted in reduced preconditioning-induced protection of the retinal photoreceptors. These data demonstrate that LIFR and its ligands play an essential role in endogenous neuroprotective mechanisms triggered by preconditioning-induced stress.
Department of Bioengineering, The University of Oklahoma, Norman, OK, USA.
Srinivas
S
Chollangi
Jiangang
J
Wang
Aaron
A
Martin
John
J
Quinn
John D
JD
Ash
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D016207:Cytokines / Q000378:metabolism; D004596:Electroretinography; D006023:Glycoproteins / Q000378:metabolism; D007700:Kinetics; D053605:Leukemia Inhibitory Factor / Q000378:metabolism; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018384:Oxidative Stress; D010775:Photic Stimulation; D020419:Photoreceptor Cells, Vertebrate / Q000502:physiology; D012333:RNA, Messenger; D011994:Recombinant Proteins / Q000378:metabolism / Q000633:toxicity; D012160:Retina / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism
D016207:Cytokines; D006023:Glycoproteins; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507838:Lif protein, mouse; C507841:Lifr protein, mouse; D012333:RNA, Messenger; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C121169:cardiotrophin-like cytokine; C092073:cardiotrophin 1