Amyloid-beta (A beta) is a hallmark component of age-related macular degeneration (AMD), which induces secretion of proinflammatory cytokines from retinal pigment epithelium (RPE). Previous studies have shown that p50/RelA (p65), a member of NF-kappa B family, is an essential pro-inflammatory transcription factor responding to A beta(1-40) stimulation, but few focused on the other two Rel transcription factor members - RelB and c-Rel - and their role in A beta(1-40)-mediated inflammation. It was reported that RelA, RelB and c-Rel are also implicated in various NF-kappa B-mediated inflammatory diseases. Therefore, we infer that A beta(1-40)-mediated inflammation targets not only the classical inflammation regulator, RelA, but also RelB and c-Rel. In this study, we demonstrate that intravitreally injected A beta(1-40) mice develop AMD-like pathologic changes, coupled with Rel protein (RelA, RelB and c-Rel) synthesis and nuclear translocation. To focus on the interaction mechanism of Rel proteins, we found that RelB and c-Rel formed a heterodimer with RelA in mice model. We also found that c-Rel silencing decreased the levels of A beta(1-40)-dependent RelA expression, indicating that RelB and c-Rel may interact with RelA as coactivator and c-Rel is required to activate the expression of RelA. Moreover, Rel protein silencing decreased the expression of distinct pro-inflammatory cytokines. Together, we demonstrate that besides RelA, RelB and c-Rel can also be activated by A beta(1-40), all of which mediate pro-inflammatory cytokine transcription and RPE damage. Our findings imply that RPE-mediated inflammation under the stimulation of A beta(1-40) is multi-targeted and RelA, RelB and c-Rel proteins may be the new targets of anti-inflammatory agents.
[1]Shanghai Jiao Tong Univ, Sch Med, Shanghai Peoples Hosp 1, Dept Ophthalmol,Shanghai Gen Hosp, Shanghai, Peoples R China.
[2]Shanghai Engn Ctr Visual Sci & Photomed, Shanghai 200080, Peoples R China.
[3]Shanghai Key Lab Fundus Dis, Shanghai, Peoples R China.
[4]Shanghai Univ Tradit Chinese Med, Shanghai Municipal Hosp Tradit Chinese Med, Dept Ophthalmol, Shanghai, Peoples R China.
[5]Yale Univ, Sch Med, Dept Pathol, 10 Amistad St, New Haven, CT 06520 USA.
[6]Shanghai Univ Tradit Chinese Med, Shanghai Geriatr Inst Chinese Med, Longhua Hosp, Shanghai, Peoples R China.
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