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 syndrom (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 2α (eIF2α), 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.

Keywords:

• astrocytes
• COX-2
• ER stress
• JNK
• retrovirus

This work was supported by NIH grants MH71583 and NS43984 (to P.K.Y.W.), NIEHS Center Grant ES07784, and NCI Core Grant CA16672. The authors thank Vanessa Edwards and Kara Waters for their assistance in preparing the manuscript. The authors also thank Dr. William S. Lynn for critical comments on the manuscript. Received 8 September 2004; revised 3 November 2004; accepted 4 November 2004.