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A.W. Taylor, D. Yee; Innate Immunity Mediated by the Toll-like Receptor(TLR)4 Is Suppressed by Ocular Immunosuppressive Cytokines . Invest. Ophthalmol. Vis. Sci. 2003;44(13):4301.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Activation of innate immunity through TLR4 on antigen presenting cells (APC, macrophages or dendritic cells) promotes APC activation of antigen-specific Th1 cells and APC anti-microbial activity. Since aqueous humor suppresses the activation of Th1 cells, we examined the potential for specific aqueous humor immunosuppressive cytokines to suppress TLR4 associated innate immune activity. Methods: Desiccated M. tuberculosis bacteria, a TLR4 activating pathogen, were added to cultures of adherent mouse spleen cells treated with the aqueous humor immunosuppressive cytokines α-MSH, VIP, CGRP, or SOM at their aqueous humor concentration. After 24 hours incubation, the adherent cells were washed and M. tuberculosis specific Th1 cells were added to the cultures. The culture supernatants were assayed 48 hours later for IFN-γ by ELISA. Cultures of the mouse monocytic leukemia cell line J774 were treated with α-MSH, VIP, CGRP or SOM and activated via the TLR4 with endotoxin. The culture supernatants were assayed for nitric oxide generation by Griess reagent. Results: APC that processed and presented antigen with TLR4 activation were suppressed in activating Th1 cells when these APC were treated with α-MSH or SOM, but not suppressed when treated with CGRP or VIP. Nitric oxide production induced by endotoxin activated J774 cells was suppressed only by α-MSH and CGRP. In regulating innate immunity, α-MSH suppressed all TLR4 associated activity, CGRP suppressed only antimicrobial activity, SOM suppressed only the promoted activation of Th1 cells, and VIP had no effect on TLR4 associated innate immunity. Conclusions: The ocular microenvironment contains a multiplicity of factors to suppress innate immune activation of Th1 cells. Each factor influences discrete stages of the interface between innate and adaptive immunity. This suggests that under conditions of uveitis, to suppresses innate and adoptive immune mediated inflammation only a few key aqueous humor cytokines need to be reintroduced.
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