Interleukin-6: A Constitutive Modulator of Glycoprotein 130, Neuroinflammatory and Cell Survival Signaling in Retina

OBJECTIVE The 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. METHODS In 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. RESULTS In 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. CONCLUSIONS 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.