Differential Expression of IL-6/gp130 Cytokines, Jak-STAT Signaling and Neuroprotection After M??ller Cell Ablation in a Transgenic Mouse Model

摘要

Purpose.: 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. M??ller 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 M??ller cell ablation in the neural retinas of adult mice. This resulted in photoreceptor apoptosis and reactive activation of surviving M??ller 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 M??ller 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 M??ller cell ablation, with concomitant increase in signal transducers and activators of transcription and extracellular kinases 1 and 2, particularly in surviving, activated M??ller cells. Basic fibroblast growth factor was robustly increased in photoreceptors after selective M??ller 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 M??ller cells are critical for their induction and action. Lack of rLIF-mediated neuroprotection contrasts with other retinal degenerations where M??ller cell integrity remains intact or photoreceptor apoptosis occurs in a more rapid, synchronous manner. The presence of M??ller cells may be critical for the functional benefits of rLIF and potentially other IL-6/gp130 cytokines.