Differential tumor necrosis factor and nitric oxide production in retinal Müller glial cells from C3H/HeN and C3H/HeJ mice

Abstract

Tumor necrosis factor (TNF) and nitric oxide (NO) have been shown to play a role in the pathogenesis of endotoxin-induced uveitis (EIU) in rats. Susceptibility to develop EIU in vivo is correlated with the extent of TNF production by retinal Müller glial cells (RMG). Moreover, RMG cells from the susceptible Lewis rat strain synthesize high amounts of nitrite under in vitro stimulation. Variations in susceptibility to endotoxin are observed among mice strains: C3H/HeN mice are known to be susceptible to develop EIU while C3H/HeJ are refractory. We show here that treatment of RMG cells from both strains with LPS + IFN-gamma does not induce TNF-synthesis in culture supernatants but produces high amounts of NO only in the supernatants from activated C3H/HeN RMG cells. The addition of TNF in the culture medium containing LPS/IFN-gamma further increases nitrite production in C3H/HeN RMG cells and allows the synthesis of low levels of nitrite in C3H/HeJ RMG cells. Addition of a specific NO synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA), blocks NO release. We have previously shown that intraperitoneal injections of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) which inhibited nitrite and TNF release in the ocular media reduced EIU in rat. We conclude here that the in vivo susceptibility to develop EIU in mice is correlated with the extent of in vitro nitrite production by RMG cells confirming the implication of NO in the induction of ocular inflammation. The low level of retinal inflammation observed during EIU in C3H/HeN mice compared to rats could be related to the absence of TNF production by RMG cells.

Neutralizing Tumor Necrosis Factor-α Activity Suppresses Activation of Infiltrating Macrophages in Experimental Autoimmune Uveoretinitis

“…However, as we have showed in the current study, macrophages generated NO after stimulation with IFN␥ alone, and thus administering sTNFr-IgG to macrophages in vitro does not block generation of NO. 29,30 IFN␥/TNF-induced NO production. How does sTNFr-IgG therapy suppress macrophage activity in vivo?…”

Tumor Necrosis Factor-α and Interleukin-6 Levels in Patients with Primary Open-Angle Glaucoma

“…Intraocular TNF-α is likely secreted from activated macrophages, astrocytes [22], microglial cells [5] and retinal Müller glial cells [23]. These results suggest that intraocular stress, including high pressure and ischemia, stimulates TNF-α production, which may signal the progression of neuronal damage.…”

Retinal Macroglial Responses in Health and Disease

“…Molecules from inflammatory cells, platelets, and plasma may activate Müller cells, and these cells may express a wide variety of inflammation- and immune-response-related factors and enzymes such as TNF- α , IL, interferon, and ICAM-1 ( Figure 3 ) [ 75 ]. Müller cells can mediate direct cytotoxic effects via an intensified expression of TNF- α or monocyte chemoattractant protein- (MCP-) 1 [ 79 , 150 – 152 ]. Notably, microglial activation induces Müller responses such as an increase in Müller cell-microglia adhesive cell contacts that may guide the intraretinal mobilization of migratory microglia in a radial direction using Müller cell processes as an adhesive scaffold [ 153 ].…”