Antineuroinflammatory effect of NF-kappaB essential modifier-binding domain peptides in the adoptive transfer model of experimental allergic encephalomyelitis.
It has been shown that peptides corresponding to the NF-kappaB essential modifier-binding domain (NBD) of IkappaB kinase alpha or IkappaB kinase beta specifically inhibit the induction of NF-kappaB activation without inhibiting the basal NF-kappaB activity. The present study demonstrates the effectiveness of NBD peptides in inhibiting the disease process in adoptively transferred experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis. Clinical symptoms of EAE were much lower in mice receiving wild-type (wt)NBD peptides compared with those receiving mutated (m)NBD peptides. Histological and immunocytochemical analysis showed that wtNBD peptides inhibited EAE-induced spinal cord mononuclear cell invasion and normalized p65 (the RelA subunit of NF-kappaB) expression within the spinal cord. Analysis of lymph node cells isolated from donor and recipient mice showed that wtNBD peptides but not mNBD peptides were able to shift the immune response from a Th1 to a Th2 profile. Consistently, wtNBD peptides but not mNBD peptides inhibited the encephalitogenicity of myelin basic protein-specific T cells. Furthermore, i.p. injection of wtNBD peptides but not mNBD peptides was also able to reduce LPS- and IFN-gamma-induced expression of inducible NO synthase, IL-1beta, and TNF-alpha in vivo in the cerebellum. Taken together, our results support the conclusion that NBD peptides are antineuroinflammatory, and that NBD peptides may have therapeutic effect in neuroinflammatory disorders such as multiple sclerosis.
Dasgupta
Subhajit
S
Section of Neuroscience, Department of Oral Biology, University of Nebraska Medical Center, Lincoln, NE 68583, USA.
Jana
Malabendu
M
Zhou
You
Y
Fung
Yiu K
YK
Ghosh
Sankar
S
Pahan
Kalipada
K
D019264:Adoptive Transfer; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D013116:Spinal Cord / Q000187:drug effects; D013154:Spleen / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D051996:Transcription Factor RelA
D000893:Anti-Inflammatory Agents; D002352:Carrier Proteins; C467063:NBD peptide, mouse; D016328:NF-kappa B; D009363:Neoplasm Proteins; D010455:Peptides; C498144:Rela protein, mouse; D051996:Transcription Factor RelA