Up-regulation of astrocyte cyclooxygenase-2, CCAAT/enhancer-binding protein, glucose-related protein 78, eukaryotic initiation factor 2α, and c-Jun N-terminal kinase by a neurovirulent murine retrovirus

Abstract

In susceptible strains of mice, infection with the mutant retrovirus MoMuLV-ts1 causes a neurodegeneration and immunodeficiency syndrome that resembles human human immunodeficiency virus-acquired immunodeficiency syndrome (HIV-AIDS). In this study the authors show increased expression of cyclooxygenase-2 (COX-2) in the brainstem tissues of ts1-infected mice. Up-regulated central nervous system (CNS) levels of this enzyme are associated with HIV-associated dementia and other inflammatory and neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. In brainstem sections, the authors find that astrocytes surrounding spongiform lesions contain increased amounts of immunoreactive COX-2. COX-2 is also up-regulated in cultured ts1-infected cells from the C1 astrocytic cell line, and activation of c-Jun N-terminal kinase, or JNK, pathway. Markers of endoplasmic reticulum (ER) stress, specifically the CCAAT/enhancer-binding protein (CHOP), the glucose-related protein 78 (GRP78), and phosphorylated eukaryotic initiation factor 2 alpha (eIF2 alpha), were also up-regulated in ts1-infected C1 astrocytes. Up-regulation of COX-2 and the above ER signaling factors was reversed by treatment of the infected cells with curcumin which specifically inhibits the JNK/c-Jun pathway. These findings indicate that the JNK/c-Jun pathway is most likely responsible for COX-2 expression induced by ts1 in astrocytes, and that ts1 infection in astrocytes may lead to up-regulation of both inflammatory and ER stress pathways in the central nervous system. Because COX-2 inhibitors are now widely used to treat inflammatory conditions in animals and humans, this finding suggests that these drugs may be useful for therapeutic intervention in neurodegenerative syndromes as well.

Retrovirus-Induced Oxidative Stress with Neuroimmunodegeneration Is Suppressed by Antioxidant Treatment with a Refined Monosodium α-Luminol (Galavit)

“…Earlier work from this laboratory established that ts1-infected cultured astrocytes show intracellular accumulation of gPr80 env , which is associated with oxidative and ER stress and depletion of GSH (24,29,45). These cells also have increased levels of markers of oxidative stress and exhibit elevated antioxidant defenses, including upregulated levels of Nrf2 and its downstream target proteins GPx and xCT, the cell surface cystine-glutamate antiporter (45).…”

“…We have shown previously that gPr80 env accumulation in the endoplasmic reticulum (ER) of ts1-infected cells causes ER stress, with release of calcium (Ca 2ϩ ) from ER stores (24,29). This in turn results in mitochondrial stress, resulting from mitochondrial membrane permeabilization, uncoupling of the respiratory chain, and cytochrome c release, followed by mitochondrial stress (23,25,29,43,54).…”

Uses for JNK: the Many and Varied Substrates of the c-Jun N-Terminal Kinases

“…There is also an increasing body of literature showing that JNK activation follows bacterial, fungal, prion, parasitic, or viral infections. Under these circumstances, JNK activation may influence important cellular consequences, such as alterations in gene expression (1,53,59,162,167,176,199,294,325,326,346), cell death (58,89,137,139,169,193,243,293), viral replication, persistent infection or progeny release (215,224,251,260), or altered cellular proliferation (178). The exact mechanism of JNK activation under each of these circumstances remains to be elucidated fully, although there may be involvement of Toll-like receptors, direct pathway modulation through interaction with upstream protein regulators, or the activation following an ER stress response (79,87,110,124,143,191,253,261,279,294,312).…”

Early Blood Profiles of Virus Infection in a Monkey Model for Lassa Fever

“…COX-2 is the key enzyme in prostaglandin biosynthesis; it is upregulated by many viruses (13,17,36,37,66,67,78), and cytomegalovirus is so dependent on COX-2 for replication that it encodes a COX-2 homologue (70). COX-2 expression can be upregulated by TNF-␣, IL-1␤, or a variety of growth factors like VEGF and EGRF (2), but virulent arenaviruses in cell culture usually downregulate such products of NF-B/RBP-mediated transcription (22,26,45).…”