myelin-basic-protein and tamibarotene

Experimental allergic encephalomyelitis (EAE) is an autoimmune model with inflammation and demyelination in the central nervous system, which resembles the human demyelinating disorder, multiple sclerosis (MS). In this study, we investigated the effect of Am-80, a synthetic retinoid, on EAE in DA rats. DA rats immunized with complete Freund's adjuvant (CFA) supplemented with myelin basic protein (MBP) developed severe EAE which reached the peak 12 to 14 days after immunization. Am-80 and prednisolone administered orally for 12 days after immunization diminished the clinical symptoms and infiltration of inflammatory cells in a dose dependent manner. However, after stopping administration, EAE recurred in DA rats treated with Am-80, but not with prednisolone. The different responses between Am-80 and prednisolone were not due to the difference in the tolerability to the MBP because both inhibited the delayed-type hypersensitivity response to MBP only during administration. To investigate the mechanism how Am-80 alone delayed the response, the expressional levels of mRNA for interleukin-6 (IL-6), interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) in spinal cord were examined. Transcriptional levels of IL-6, IFN-gamma and TNF-alpha were parallel with the clinical symptoms of the disease in Am-80-treated rats, that is, expressional levels of their mRNA were diminished during the administration of Am-80, which then increased as soon as the administration was stopped. Among them, the expression of IL-6 mRNA was more rapidly and highly relapsed than that of the other two cytokines mRNA. However, prednisolone attenuated transcriptions of all these cytokines throughout the experiment. Therefore, these findings suggested that the inhibition of EAE is, in part, related to the inhibition of IL-6 production. However, there are many possible mechanism in the suppression of EAE by Am-80, further experiments will be necessary.

Topics: Administration, Oral; Animals; Benzoates; Disease Models, Animal; Dose-Response Relationship, Drug; Ear, External; Encephalomyelitis, Autoimmune, Experimental; Female; Hypersensitivity, Delayed; Interferon-gamma; Interleukin-6; Myelin Basic Protein; Prednisolone; Rats; Recurrence; Retinoids; RNA, Messenger; Spinal Cord; Tetrahydronaphthalenes; Tumor Necrosis Factor-alpha

To observe the role of interleukin (IL)-6 in the development of experimental autoimmune encephalomyelitis (EAE).. DA rats were immunized by injecting bovine myelin basic protein (MBP). mRNA of cytokines, such as IL-6, IL-10, TNF-alpha, TGF-beta 1, IFN-gamma, and iNOS, were detected by RT-PCR. MBP was injected into ear to induce delayed type cutaneous hypersensitivity response (DTH). Histological studies were performed on the spinal cord with HE staining. Nitric oxide (NO) production from cultured murine macrophage clones was stimulated with LPS plus IFN-gamma.. DA rats developed EAE disease with a peak of severity on d 13 and d 14. Am-80 (1.0, 3.0 mg/kg), a selective IL-6 inhibitor, inhibited the symptoms in terms of deterioration as observed by the clinical score, body weight and histological findings, in a dose-related manner. A high dose of Am-80 (3.0 mg/kg for 12 d) did not completely inhibit the disease, but delayed the symptoms and enhanced the delayed response. By prolonging the duration of treatment (18 d), Am-80 inhibited the onset of EAE during administration, but the symptoms of EAE appeared after the administration was stopped. Am-80 administerd for 12 d inhibited the DTH response on d 11 but not on d 22. RT-PCR studies demonstrated a strong expression of IFN-gamma, IL-6, IL-10, TGF-beta 1, TNF-alpha, and iNOS mRNA in spinal cord 13 d after immunization. However IFN-gamma, IL-10, TNF-alpha, and iNOS mRNA expression (on d 13) was suppressed by Am-80, except in the case of IL-6, hence the effect of Am-80 on the expression of IL-6 mRNA was examined in additional experiments. After Am-80 was administered for 12 d or 18 d, the expression of IL-6 mRNA was inhibited on d 12 or d 18, but increased on d 13 or d 19, respectively.. These findings suggest that inhibition of EAE by Am-80 is initiated by inhibition of IL-6 production.

Topics: Animals; Benzoates; Cytokines; Encephalomyelitis, Autoimmune, Experimental; Female; Interferon-gamma; Interleukin-10; Interleukin-6; Myelin Basic Protein; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Rats; RNA, Messenger; Spinal Cord; Tetrahydronaphthalenes