Nitric oxide-induced immune switching in experimental inflammatory autoimmune diseases

ABSTRACT

BACKGROUND: Nitric oxide (NO) production has been described as a double-edged sword eliciting both pro-and anti-inflammatory effect s in different immune reactions. This work was undertaken to investigate the immunoregulatory role of NO in experimental allergic encephalomyelitis (EAE) and experimental allergic uveitis (EAU). MEHHOD We examined whether molsidomine (MSDM), a NO donor, administration to the myelin basic protein (MBP)-or interphotoreceptor retinoid binding protein (IRBP)-immunized rat s could suppress EAE development by shifting toward the Th2 cytokine response. In the EAE experiment s, the rat s were treated orally with MSDM (10 mg/kg/day) at the early stage (-1-4 days) or throughout the experimental period (-1-15 days). RESULTS: This resulted in significant amelioration of the disease and mild clinical symptoms, while MBP-immunization without MSDM administration showed severe EAE development . A marked reduction in inflammation was also observed in the spinal cord, indicating the crucial role of NO in the pathogenesis of EAE in in vivo. In the EAU experiments, a 24 h pre-treatment with MSDM prior to IRBP immunization resulted in significant inhibition of the disease. Furthermore, MSDM administration for 2 1 days completely reduced the incidence and severity of EAU. To investigate whether MSDM could modulate cytokine switching from Th 1 to Th2, culture supernatants of MBP-or IRBP-stimulated inguinal lymphocytes were analyzed. MSDM treatment enhanced IL-10 secretion but decreased IFN-gamma. IL-4 was undetectable in all groups. In contrast, the MBP-or IRBP-immunized rat s without MSDM secreted high concentrations of IFN-gamma, but low concentrations of IL-10. CONCLUSION: In conclusion, NO administation suppresses EAE and EAU by modulating the Th 1/Th2 balance during inflammatory immune responses. This work further suggest s that NO may be useful in the therapeutic control of autoimmune disease.