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Tumor necrosis factor and nitric oxide production by retinal Müller glial cells from rats exhibiting inherited
Abstract:
The primary cause of the inherited retinal dystrophy observed in Royal College of Surgeons (RCS) rats is located in the retinal pigmented epithelium, which is unable to phagocytize photoreceptor outer segments. We have demonstrated here that retinal Müller glial (RMG) cells obtained from RCS dystrophic rats and stimulated in vitro with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) accumulated higher levels of tumor necrosis factor (TNF) and inducible nitric oxide synthase (NOS II) mRNA and released in culture supernatants significantly higher amounts of TNF and nitrite compared to cells derived from nondystrophic controls. The TNF and NOS II mRNA expression and TNF and nitrite synthesis induced in RMG cells from both strains by LPS + IFN-gamma was significantly prevented by including transforming growth factor-beta (TGF-beta) in the culture medium. Coincubation of the stimulants with an inhibitor of NOS II, NG-monomethyl-L-arginine (L-NMMA), while inhibiting nitrite synthesis, induced an increase of TNF production in supernatants from RMG cells without increasing TNF mRNA levels. The retinal dystrophy observed in RCS dystrophic rats could result from an abnormal susceptibility of RMG cells form RCS dystrophic rats to produce TNF and NO in response to stimulants. Administration of the immunomodulatory cytokine TGF-beta or inhibitors of NOS II would provide additional research avenues for photoreceptor rescue.
Insights
Retinal Müller glial cells from dystrophic rats overproduce inflammatory factors like tumor necrosis factor (TNF) and nitric oxide (NO). Transforming growth factor-beta (TGF-beta) can prevent this, offering potential therapies for inherited retinal dystrophy.
Area of Science:
- Ophthalmology
- Neuroscience
- Immunology
Background:
- Inherited retinal dystrophy in Royal College of Surgeons (RCS) rats stems from retinal pigmented epithelium dysfunction.
- This dysfunction impairs photoreceptor outer segment phagocytosis, leading to vision loss.
Purpose of the Study:
- To investigate the inflammatory response of retinal Müller glial (RMG) cells from RCS rats.
- To explore the role of specific inflammatory mediators in the pathogenesis of inherited retinal dystrophy.
Main Methods:
- RMG cells from RCS and control rats were stimulated in vitro with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma).
- Levels of tumor necrosis factor (TNF) and inducible nitric oxide synthase (NOS II) mRNA and protein were quantified.
- The effects of transforming growth factor-beta (TGF-beta) and NG-monomethyl-L-arginine (L-NMMA) were assessed.
Main Results:
- RMG cells from RCS rats showed significantly higher accumulation of TNF and NOS II mRNA and release of TNF and nitrite compared to controls.
- TGF-beta significantly prevented LPS + IFN-gamma-induced TNF and NOS II expression and TNF/nitrite synthesis.
- L-NMMA inhibited nitrite synthesis and increased TNF production without altering TNF mRNA levels.
Conclusions:
- Abnormal susceptibility of RMG cells in RCS rats to produce TNF and NO may contribute to retinal dystrophy.
- TGF-beta and NOS II inhibitors represent potential therapeutic strategies for photoreceptor rescue in inherited retinal dystrophies.