STAT3 activation in photoreceptors by leukemia inhibitory factor is associated with protection from light damage

Abstract

Members of the interleukin‐6 cytokine family, including leukemia inhibitory factor (LIF), signal through gp130. The neuroprotective role of gp130 activation has been widely demonstrated in both CNS and PNS, but the mechanism by which this is accomplished is not well established. We investigated temporal and cell‐specific activation of signaling pathways induced by LIF in the mature mouse retina. Intravitreal injection of LIF preserved photoreceptor function and prevented photoreceptor cell death from light‐induced oxidative damage in a dose‐dependent manner (2 days post‐injection). A therapeutic dose of LIF induced rapid and sustained activation of signal transducer and activator of transcription (STAT) 3. Activated STAT3 was localized to all the retinal neurons and glial cells, including photoreceptors. Activation of extracellular signal‐regulated kinase 1 and 2 was robust but transient in Müller glial cells, and undetectable at the time of light exposure. Akt was not activated by LIF. We also show that at the time of neuroprotection, STAT3 but not extracellular signal‐regulated kinase 1 and 2 or the Akt pathways was active in LIF‐treated retinas, and activated STAT3 was clearly localized in transcriptionally active areas of photoreceptor nuclei. Our data suggest that photoreceptor protection in response to LIF can be directly mediated by activation of STAT3 in photoreceptors.

Leukemia Inhibitory Factor Extends the Lifespan of Injured PhotoreceptorsIn Vivo

“…A similar retinal response has been observed in models of inherited retinal degeneration (Samardzija et al, 2006a). Since recombinant LIF can protect photoreceptor cells against light-induced degeneration (Ueki et al, 2008), the increased expression of endogenous LIF in response to damaging light suggests that LIF might be part of a retinal defense mechanism to increase survival of visual cells. Such an endogenous protective response has recently been postulated by Rattner and Nathans.…”

“…Similarly to GFAP in Muller cells, phosphorylation of the antiapoptotic STAT3 protein has been commonly observed during degenerative processes in the retina (Mechoulam and Pierce, 2005;Samardzija et al, 2006a;Yang et al, 2007;Ueki et al, 2008). As for the increased GFAP expression, phosphorylation of STAT3 was completely blocked in retinas of VPP;Lif -/-mice (Fig.…”

“…It has been shown that injection of rLIF protects the retina against a toxic insult (Ueki et al, 2008), that injection of rLIF upregulates endogenous FGF2 in the retina (Fig. 6), that increased expression of endogenous FGF2 protects against retinal degeneration (O'Driscoll et al, 2008) and that lack of FGF2 activation correlates with accelerated photore- ceptor death (Figs.…”

“…Since LIF-R and gp130, the two receptor subunits required for LIF binding are ubiquitously expressed in the retina including photoreceptors (Ueki et al, 2008) LIF may directly target visual cells to increase Edn2 production. This notion is supported by our observation that injection of rLIF into eyes of mice without photoreceptors (aged rd1 mice) did not provoke a similar strong response (Fig.…”

A Unique Loop Structure in Oncostatin M Determines Binding Affinity toward Oncostatin M Receptor and Leukemia Inhibitory Factor Receptor

“…This improvement in OSM's function could prove valuable in treating diseases associated with melanoma. Previous research in our laboratory has shown that STAT3 activation induced by IL-6 family cytokines, including OSM, is neuroprotective and prevents photoreceptor cell death under oxidative stress (38,39). The mutant OSM molecules, OSM-M1 and OSM-M2, could thus serve as potent therapeutic agents in preventing photoreceptor degeneration induced by oxidative stress, e.g.…”