Differential Expression of IL-6/gp130 Cytokines, Jak-STAT Signaling and Neuroprotection After Müller Cell Ablation in a Transgenic Mouse Model.
OBJECTIVE
It is anticipated that the interleukin-6/glycoprotein 130 (IL-6/gp130) family of cytokines and Jak-STAT signaling may be amenable to therapeutic manipulation for retinal diseases. Müller cells, which exhibit morphologic and functional changes in prevalent retinal diseases, are implicated in their induction and action.


METHODS
We characterized expression of endogenous IL-6/gp130 cytokines and Jak-STAT signaling after inducible Müller cell ablation in the neural retinas of adult mice. This resulted in photoreceptor apoptosis and reactive activation of surviving Müller cells. Analysis was performed by using a combination of quantitative real-time polymerase chain reaction, Western blot, and immunohistochemistry. Recombinant leukemia inhibitory factor (rLIF) was intravitreally injected in an attempt to inhibit photoreceptor degeneration following selective Müller cell ablation.


RESULTS
Significant differential expression (both increases and decreases) of multiple IL-6/gp130 cytokines, such as LIF, oncostatin-M, and ciliary neurotrophic factor, occurred after Müller cell ablation, with concomitant increase in signal transducers and activators of transcription and extracellular kinases 1 and 2, particularly in surviving, activated Müller cells. Basic fibroblast growth factor was robustly increased in photoreceptors after selective Müller cell ablation. Multiple injections of rLIF failed to prevent photoreceptor degeneration.


CONCLUSIONS
These results further characterize expression of IL-6/gp130 cytokines and Jak-STAT signaling in outer retinal disease, suggesting Müller cells are critical for their induction and action. Lack of rLIF-mediated neuroprotection contrasts with other retinal degenerations where Müller cell integrity remains intact or photoreceptor apoptosis occurs in a more rapid, synchronous manner. The presence of Müller cells may be critical for the functional benefits of rLIF and potentially other IL-6/gp130 cytokines.
Nathan J
NJ
Coorey
Weiyong
W
Shen
Ling
L
Zhu
Mark C
MC
Gillies
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D050822:Cytokine Receptor gp130 / Q000096:biosynthesis / Q000235:genetics*; D004195:Disease Models, Animal; D063928:Ependymoglial Cells / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D012162:Retinal Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction
D050796:STAT3 Transcription Factor; D050822:Cytokine Receptor gp130; D012313:RNA