The NF-B/Rel family of transcription factors plays a key role in regulating inflammatory and immune responses and other programs of cell growth and survival. The five known mammalian Rel genes encode seven Rel-related proteins: RelA/p65; p105 and its processing product, p50; p100 and its processing product, p52; c-Rel; and RelB. Each contains an N-terminal Rel homology domain (ϳ300 amino acids) that mediates DNA binding, dimerization, and interaction with the IB family of NF-B/Rel inhibitors. RelA, c-RelA, and RelB contain C-terminal transactivation domains, but p50 and p52 do not. Each NF-B/Rel protein forms different homo-or heterodimers with other members of the family, which may contribute to the activation of specific target genes (1, 5).The prototypical NF-B complex is a p50/RelA heterodimer. NF-B is largely sequestered in the cytoplasm through its association with an IB inhibitor. Nuclear NF-B expression is induced by various stimuli, including proinflammatory cytokines, growth factors, DNA-damaging agents, and viral proteins (13). The activation of NF-B can be divided into two phases. The first phase involves cytoplasmic events culminating in the activation of the IB kinases (IKK1 and IKK2). These kinases promote N-terminal phosphorylation of serines 32 and 36 in IB␣, leading to its polyubiquitylation and proteasome-mediated degradation. The liberated NF-B complex rapidly translocates to the nucleus, ending the first phase (13). The second phase occurs primarily in the nucleus and involves posttranslational modification of the NF-B transcription factor complex or relevant histones surrounding NF-B target genes (5). These modifications determine both the strength and duration of the NF-B-mediated transcriptional response (5).One of the nuclear events is the reversible acetylation of RelA (4). Endogenous RelA is acetylated in a stimulus-coupled manner after activation of cells with tumor necrosis factor alpha (TNF-␣), phorbol myristate acetate, or other stimuli at multiple sites, including lysines 122, 123, 218, 221, and 310 (4, 17). The acetyltransferases p300 and CBP appear to play a major role in the in vivo acetylation of RelA (6,17). Sitespecific acetylation of RelA regulates discrete biological actions of the NF-B complex (5, 6). For example, acetylation of lysine 221 by p300/CBP increases the DNA binding affinity of RelA for the B enhancer and, together with acetylation of lysine 218, impairs assembly of RelA with newly synthesized IB␣, which shuttles in and out of the nucleus. Acetylation of lysine 310 does not modulate DNA binding or IB␣ assembly but markedly enhances the transcriptional activity of NF-B. Deacetylation of lysine 310 by histone deacetylase 3 (HDAC3) or SIRT1 inhibits the transcriptional activity of RelA and augments cellular apoptosis in response to 32). While it is clear that signal-coupled acetylation of RelA participates in the nuclear regulation of NF-B action (4, 17), many unanswered questions remain. Chief among these is how the acetylation of RelA is regulated.

CD28 and CTLA-4 are related members of a family of T lymphocyte cell surface receptors that function to regulate T cell activation. We have found that the cytoplasmic domains of both CTLA-4 and CD28 can associate with members of the PP2A family of serine/threonine phosphatases. The association of PP2A with CD28 was negatively regulated by tyrosine phosphorylation of the CD28 cytoplasmic domain. Inhibition of PP2A activity in Jurkat leukemia T cells by treatment with okadaic acid or by expression of a dominant-negative mutant enhanced T cell activation induced by CD28 engagement. Interactions between cell surface receptors such as CTLA-4 and CD28 and serine/threonine phosphatases may represent a novel mechanism for modulating the intracellular signal transduction pathways associated with cell activation.

Summary Although inflammation in the brain is meant as a defense mechanism against neurotoxic stimuli, increasing evidence suggests that uncontrolled, chronic and persistent inflammation contributes to neurodegeneration. Most neurodegenerative diseases have now been associated with chronic inflammation, including Alzheimer’s disease (AD). Whether anti-inflammatory approaches can be used to treat AD, however, is a major unanswered question. We recently demonstrated that monoacylglycerol lipase (MAGL) hydrolyzes endocannabinoids to generate the primary arachidonic acid pool for neuroinflammatory prostaglandins. In this study, we show that genetic inactivation of MAGL attenuates neuroinflammation and lowers amyloid βlevels and plaques, in an AD mouse model. We also find that pharmacological blockade of MAGL recapitulates the cytokine lowering effects through reduced prostaglandin production, rather than enhanced endocannabinoid signaling. Our findings thus reveal a heretofore unrecognized role of MAGL in modulating neuroinflammation and amyloidosis in AD etiology, and put forth MAGL inhibitors as a potential next-generation strategy for combatting AD.

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Despite the important role of apolipoprotein E (apoE) secretion from astrocytes in brain lipid metabolism and the strong association of apoE4, one of the human apoE isoforms, with sporadic and late onset forms of Alzheimer’s disease (AD) little is known about the regulation of astrocytic apoE. Utilizing annotated chemical libraries and a phenotypic screening strategy that measured apoE secretion from a human astrocytoma cell line, inhibition of pan class I histone deacetylases (HDACs) was identified as a mechanism to increase apoE secretion. Knocking down select HDAC family members alone or in combination revealed that inhibition of the class I HDAC family was responsible for enhancing apoE secretion. Knocking down LXRα and LXRβ genes revealed that the increase in astrocytic apoE in response to HDAC inhibition occurred via an LXR-independent pathway. Collectively, these data suggest that pan class I HDAC inhibition is a novel pathway for regulating astrocytic apoE secretion.