RESUMEN
The pro-inflammatory activity of interleukin 17, which is produced by the IL-23/IL-17 axis, has been associated with the pathogenesis of traumatic brain injury (TBI). The study investigated the potential role of IL-17 in secondary brain injury of TBI in a rat model. Our data showed that the levels of IL-17 increased from 6 h to 7 days and peaked at 3 days, in both the CNS and serum, which were consistent with the severity of secondary brain injury. The IL-23 inhibitor suberoylanilide hydroxamic acid (SAHA) treatment markedly decreased the expressions of IL-17 and apoptosis-associated proteins cleaved caspase-3 and increased the protein ratio of Bcl-2 (B cell lymphoma/leukemia-2)/Bax (Bcl-2-associated X protein). Meanwhile, neuronal apoptosis was reduced, and neural function was improved after SAHA treatment. This study suggests that IL-17 is involved in secondary brain injury after TBI. Administering an IL-23 inhibitor and thereby blocking the IL-23/IL-17 axis may be beneficial in the treatment of TBI.
Asunto(s)
Daño Encefálico Crónico/fisiopatología , Lesiones Traumáticas del Encéfalo/fisiopatología , Interleucina-17/fisiología , Animales , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/biosíntesis , Proteínas Reguladoras de la Apoptosis/genética , Daño Encefálico Crónico/etiología , Daño Encefálico Crónico/metabolismo , Daño Encefálico Crónico/prevención & control , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/uso terapéutico , Inflamación , Interleucina-17/sangre , Interleucina-17/líquido cefalorraquídeo , Interleucina-17/genética , Interleucina-23/antagonistas & inhibidores , Interleucina-23/fisiología , Masculino , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/sangre , Proteínas del Tejido Nervioso/líquido cefalorraquídeo , Proteínas del Tejido Nervioso/genética , Neuronas/patología , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , VorinostatRESUMEN
We have recently reported that calreticulin (CRT), a luminal resident protein, can be found in the sera of patients with rheumatoid arthritis and also that recombinant CRT (rCRT) exhibits extraordinarily strong immunological activities. We herein further demonstrate that rCRT fragments 18-412 (rCRT/18-412), rCRT/39-272, rCRT/120-308 and rCRT/120-250 can self-oligomerize in solution and are 50-100 fold more potent than native CRT (nCRT, isolated from mouse livers) in activating macrophages in vitro. We narrowed down the active site of CRT to residues 150-230, the activity of which also depends on dimerization. By contrast, rCRT/18-197 is almost completely inactive. When rCRT/18-412 is fractionated into oligomers and monomers by gel filtration, the oligomers maintain most of their immunological activities in terms of activating macrophages in vitro and inducing specific antibodies in vivo, while the monomers were much less active by comparison. Additionally, rCRT/18-412 oligomers are much better than monomers in binding to, and uptake by, macrophages. Inhibition of macrophage endocytosis partially blocks the stimulatory effect of rCRT/18-412. We conclude that the immunologically active site of CRT maps between residues 198-230 and that soluble CRT could acquire potent immuno-pathological activities in microenvironments favoring its oligomerization.