Human immunodeficiency virus type 1 (HIV-1) infection is known to cause neuronal injury and dementia in a significant proportion of patients. However, the mechanism by which HIV-1 mediates its deleterious effects in the brain is poorly defined. The present study was undertaken to investigate the effect of the HIV-1 tat gene on the expression of inducible nitric-oxide synthase (iNOS) in human U373MG astroglial cells and primary astroglia. Expression of the tat gene as RSV-tat but not that of the CAT gene as RSV-CAT in U373MG astroglial cells led to the

It has been shown that peptides corresponding to the NF-κB essential modifier-binding domain (NBD) of IκB kinase α or IκB kinase β specifically inhibit the induction of NF-κB activation without inhibiting the basal NF-κB 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-κB) 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-γ-induced expression of inducible NO synthase, IL-1β, and TNF-α 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.

The present study was undertaken to explore the role of interleukin-12 (IL-12) p40 in the expression of TNF-a in microglia. Interestingly, we have found that IL-12 p70, p40 2 (the p40 homodimer) and p40 (the p40 monomer) dosedependently induced the production of TNF-a and the expression of TNF-a mRNA in BV-2 microglial cells. In addition to BV-2 microglial cells, p70, p40 2 and p40 also induced the production of TNF-a in mouse primary microglia and peritoneal macrophages. As the activation of both NF-jB and CCAAT/enhancer binding protein b (C/EBPb) is important for the expression of TNF-a in microglial cells, we investigated the effect of p40 on the activation of NF-jB as well as C/EBPb. Activation of NF-jB as well as C/EBPb by p40 and inhibition of p40-induced expression of TNF-a by Dp65, a dominant-negative mutant of p65, and DC/EBPb, a dominantnegative mutant of C/EBPb, suggests that p40 induces the expression of TNF-a through the activation of NF-jB and C/EBPb. In addition, we show that p40 induced the activation of both extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK). Interestingly, PD98059, an inhibitor of ERK, inhibited p40-induced expression of TNF-a through the inhibition of C/EBPb, but not that of NF-jB, whereas SB203580, an inhibitor of p38 MAPK, inhibited p40-induced expression of TNF-a through the inhibition of both NF-jB and C/EBPb. This study delineates a novel biological function of p40 in inducing TNF-a in microglia and macrophages.

The presence of neuroantigen-primed T cells recognizing self-myelin antigens within the CNS is necessary for the development of demyelinating autoimmune disease like multiple sclerosis. This study was undertaken to investigate the role of myelin basic protein (

Experimental allergic encephalomyelitis (EAE) is the animal model for multiple sclerosis. The present study underlines the importance of sodium phenylacetate (NaPA), a drug approved for urea cycle disorders, in inhibiting the disease process of adoptively transferred EAE in female SJL/J mice at multiple steps. Myelin basic protein (MBP)-primed T cells alone induced the expression of NO synthase (iNOS) and the activation of NF-κB in mouse microglial cells through cell-cell contact. However, pretreatment of MBP-primed T cells with NaPA markedly inhibited its ability to induce microglial expression of iNOS and activation of NF-κB. Consistently, adoptive transfer of MBP-primed T cells, but not that of NaPA-pretreated MBP-primed T cells, induced the clinical symptoms of EAE in female SJL/J mice. Furthermore, MBP-primed T cells isolated from NaPA-treated donor mice were also less efficient than MBP-primed T cells isolated from normal donor mice in inducing iNOS in microglial cells and transferring EAE to recipient mice. Interestingly, clinical symptoms of EAE were much less in mice receiving NaPA through drinking water than those without NaPA. Similar to NaPA, sodium phenylbutyrate, a chemically synthesized precursor of NaPA, also inhibited the disease process of EAE. Histological and immunocytochemical analysis showed that NaPA inhibited EAE-induced spinal cord mononuclear cell invasion and normalized iNOS, nitrotyrosine, and p65 (the RelA subunit of NF-κB) expression within the spinal cord. Taken together, our results raise the possibility that NaPA or sodium phenylbutyrate taken through drinking water or milk may reduce the observed neuroinflammation and disease process in multiple sclerosis patients.