Abstract
ObjectiveThe interleukin-6 (IL-6) family of cytokines and their signal transducer glycoprotein (gp130) are implicated in inflammatory and cell survival functions in glaucoma. There are several avenues for interdependent modulation of IL-6 family members and gp130 signaling. Here we investigated whether IL-6 modulates gp130 and related neuroinflammatory, cell survival and regulatory signaling in both healthy and glaucomatous retina.MethodsIn naïve and glaucomatous (Microbead Occlusion Model), wildtype (WT) and IL-6 knockout (IL-6−/−) mice, we examined gp130 protein expression and localization, using western blot and immunohistochemistry. Gene targets related to IL-6 and gp130 signaling and pertinent to neuroinflammation (TNFα, IL-1β), cell health (Bax, Bcl-xl) and STAT3 regulation (Socs3) were quantified using qRTPCR.ResultsIn the naïve retina, IL-6−/− retina contained significantly less gp130 compared to WT retina. This IL-6-related decrease in gp130 was accompanied by a reduction in mRNA expression of TNFα, Socs3 and Bax. After 4 weeks of microbead-induced ocular hypertension, both microbead- and saline-injected (control) eyes of IL-6−/− mice exhibited higher expression of TNFα, compared to WT mice. IL-1β expression was also reduced specifically in IL-6−/− retina with microbead-induced glaucoma. While saline and microbead injection increased Bcl-xl and Socs3 mRNA in both WT and IL-6−/− mice, IL-6−/− deficiency led to smaller increases for both Bcl-xl and Socs3.ConclusionsOur findings support a role for IL-6 in setting baseline parameters for neuroinflammatory, cell health and gp130 regulatory signaling that can impact the nature and magnitude of retinal responses to glaucoma-related stressors.
Highlights
IL-6 mediates diverse cellular functions that are not limited to pathological inflammation [1]
In the naïve retina, IL-6−/− retina contained significantly less gp130 compared to WT retina
Our findings support a role for IL-6 in setting baseline parameters for neuroinflammatory, cell health and gp130 regulatory signaling that can impact the nature and magnitude of retinal responses to glaucoma-related stressors
Summary
IL-6 mediates diverse cellular functions that are not limited to pathological inflammation [1]. Activation of gp130 leads to a myriad of signal transduction cascades, including JAK/STAT, that drives transcription of genes associated with cell health and survival, neuroinflammation and regulation of gp130mediated signaling (Figure 1) [1,2]. Other IL-6 family members, including CNTF, IL-11, OSM and CLCF1, are associated with optic nerve regeneration [5,6,7]. Recent literature indicates that gp130-mediated activation of JAK/ STAT pathways, which can be accomplished with all IL-6 family members, is a modulator of axon regeneration in the optic nerve [7,8]. We determined that the IL-6 family of cytokines is relevant for RGC degeneration in glaucoma. Other groups have reported similar findings, including pro-survival functions for other IL-6 family members, i.e. CNTF, in glaucoma [13,14]
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