15-deoxy-Δ¹²,¹4 -prostaglandin J2 inhibits human immunodeficiency virus-1 tat-induced monocyte chemoattractant protein-1/CCL2 production by blocking the extracellular signal-regulated kinase-1/2 signaling pathway independently of peroxisome proliferator-activated receptor-γ and heme oxygenase-1 in rat hippocampal slices.

Human immunodeficiency virus (HIV)-induced inflammation, and its consequences within the central nervous system (CNS), must be countered by multiple pharmacologic agents, and 15-deoxy-Δ(12,14) -prostaglandin J(2) (15d-PGJ2) may hold promise in the treatment of pathologies associated with this inflammatory response. 15d-PGJ2 can repress the inflammatory response by means of peroxisome proliferator-activated receptor-γ (PPARγ)-dependent and -independent mechanisms. However, its precise role and antiinflammatory mechanism in the hippocampus remain poorly understood. In the present study, rat hippocampal slices were stimulated with full-length HIV-1 Tat protein to investigate the role of 15d-PGJ2 8in the hippocampal inflammatory response. Pretreatment of slices with 15d-PGJ2 markedly reduced Tat-induced monocyte chemoattractant protein-1 (MCP-1/CCL2) production. Interestingly, the PPARγ antagonist GW9662 did not inhibit action of 15d-PGJ2, confirming the latter's PPARγ-independent mechanism of mediating antiinflammatory effects. Despite 15d-PGJ2's increasing the expression of heme oxygenase-1 (HO-1), its action was not abrogated by the HO-1 inhibitor zinc protoporphyrin IX (ZnPPIX), nor was it recapitulated by HO-1 inducers such as cobalt protoporphyrin (CoPP). Moreover, short interfering RNA (siRNA)-directed knockdown of HO-1 did not abolish the antiinflammatory action of 15d-PGJ2 against Tat-induced MCP-1 production in human microglia-like THP-1 cells. Conversely, 15d-PGJ2 suppressed Tat-induced ERK1/2 activation, decreasing MCP-1 production upon Tat stimulation. The NADPH oxidase inhibitors DPI and apocynin also abrogated Tat-stimulated ERK1/2 activation, reducing MCP-1 production. Collectively, these data demonstrate that the antiinflammatory effects of 15d-PGJ2 on the hippocampus are exerted through inhibition of Tat-mediated ERK1/2 activation, coupled with that of a redox-sensitive pathway, independent of PPARγ and HO-1.

Molecular mechanisms underlying cyclic AMP inhibition of macrophage dependent TNF-alpha production and neurotoxicity in response to amyloidogenic C-terminal fragment of Alzheimer's amyloid precursor protein.

In the present study, we characterized the intracellular pathway involved in the macrophage production of tumor necrosis factor-alpha (TNF-alpha) and the molecular mechanisms by which cyclic AMP (cAMP) regulates the neurotoxic inflammatory signaling cascade in response to the 105 amino acid carboxyl-terminal fragment (CT105) of amyloid precursor protein, a candidate of alternative toxic elements in Alzheimer's disease (AD) pathology. CT105 in combination with interferon-gamma (IFN-gamma) elicited a robust and sustained increase of TNF-alpha production due to enhanced TNF-alpha mRNA transcription, mediated via increased nuclear factor-kappaB (NF-kappaB) in human macrophages derived from monocytic THP-1 cells. A mechanistic analysis revealed that the cAMP analog, dibutyryl cyclic AMP (dbcAMP), or the adenyl cyclase activator, forskolin, effectively suppressed the stimulant-induced TNF-alpha production by reducing the nuclear translocation and DNA binding activity of NF-kappaB. The inhibitory mechanisms manifested by dbcAMP included the decreased phosphorylation/degradation of NF-kappaB inhibitor (IkappaB) followed by its increased synthesis/stability. Importantly, this macrophage derived TNF-alpha appears to be a key pathological mediator of the resultant neurotoxicity, which was attenuated by increased cAMP levels during macrophage stimulation with CT105. These findings provide evidence, which supports an important role of CT105 as a potent macrophage stimulator eliciting NF-kappaB-mediated inflammatory signals for excess TNF-alpha production, which in turn ultimately leads to the neurotoxicity. In addition, the detailed inhibitory mechanism of cAMP action implies that an increased cAMP level could be benefit against AD progression.