Extracellular HIV-Tat Induces Cyclooxygenase-2 in Glial Cells through Activation of Nuclear Factor of Activated T Cells

Blanco, Almudena; Álvarez, Susana; Fresno, Manuel; Muñoz‐Fernández, María Ángeles

doi:10.4049/jimmunol.180.1.530

Cited by 20 publications

(22 citation statements)

References 75 publications

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“…HIV-1 increases COX-2 expression in the T lymphocytes and macrophages that it infects (20,21,23,25). The HIV-1 transcription factor Tat stimulates COX-2 transcription (44). HIV-1 infection can also increase plasma cytokines including IL-6 and TNFα (45, 46).…”

Section: Discussionmentioning

confidence: 99%

The Effect of HIV and HPV Coinfection on Cervical COX-2 Expression and Systemic Prostaglandin E2 Levels

Fitzgerald

Bezak

Ocheretina

et al. 2012

Cancer Prevention Research

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Human immunodeficiency virus (HIV-1) infection causes chronic inflammation. COX-2 derived prostaglandin E2 (PGE2) has been linked to both inflammation and carcinogenesis. We hypothesized that HIV-1 could induce COX-2 in cervical tissue and increase systemic PGE2 levels and that these alterations could play a role in AIDS-related cervical cancer. Levels of cervical COX-2 mRNA and urinary PGE-M, a biomarker of systemic PGE2 levels, were determined in 17 HIV-negative women with a negative cervical HPV test, 18 HIV-infected women with a negative HPV test, and 13 HIV-infected women with cervical HPV and high-grade squamous intraepithelial lesions on cytology. Cervical COX-2 levels were significantly associated with HIV and HPV status (P=0.006 and 0.002, respectively). Median levels of urinary PGE-M were increased in HIV-infected compared to uninfected women (11.2 ng/mg creatinine vs. 6.8 ng/mg creatinine, P=0.02). Among HIV infected women, urinary PGE-M levels were positively correlated with plasma HIV-1 RNA levels (P<0.001). Finally, levels of cervical COX-2 correlated with urinary PGE-M levels (P=0.005). This study demonstrates that HIV-1 infection is associated with increased cervical COX-2 and elevated systemic PGE2 levels. Drugs that inhibit the synthesis of PGE2 may prove useful in reducing the risk of cervical cancer or systemic inflammation in HIV infected women.

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Section: Discussionmentioning

confidence: 99%

The Effect of HIV and HPV Coinfection on Cervical COX-2 Expression and Systemic Prostaglandin E2 Levels

Fitzgerald

Bezak

Ocheretina

et al. 2012

Cancer Prevention Research

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“…EMSA showed that PTH stimulated NFATc1 but not NFATc2–4 binding to a sequence spanning the composite site and that NFAT played a dominant role in the cooperative binding of NFAT and AP‐1 proteins to the composite site. Binding of NFAT and AP‐1 proteins to a composite NFAT / AP‐1 site is reported to be important in the regulation of expression of cytokine and surface receptor genes in immunocytes16, 46 and in the induction of COX‐2 by PMA and calcium ionophore in human T‐lymphocytes21 and by HIV‐Tat in glial cells 47. Our data indicate that this composite NFAT / AP‐1 element is also important for COX‐2 induction by PTH in osteoblasts and that constitutively active NFATc1 can enhance the basal and PTH‐stimulated expression of COX‐2 in osteoblast cultures.…”

Section: Discussionmentioning

confidence: 99%

Parathyroid hormone induction of cyclooxygenase-2 in murine osteoblasts: Role of the calcium-calcineurin-NFAT pathway

Huang

Chikazu

Voznesensky

et al. 2010

Journal of Bone and Mineral Research

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Murine MC3T3-E1 and MC-4 cells were stably transfected with −371/+70 bp of the murine cyclooxygenase-2 (COX-2) promoter fused to a luciferase reporter (Pluc371) or with Pluc371 carrying site-directed mutations. Mutations were made in (1) the cAMP response element (CRE) at −57/−52 bp, (2) the activating protein-1 (AP-1)–binding site at −69/−63 bp, (3) the nuclear factor of activated T-cells (NFAT)–binding site at −77/−73 bp, and (4) both the AP-1 and NFAT sites, which comprise a composite consensus sequence for NFAT/AP-1. Single mutation of CRE, AP-1, or NFAT sites decreased parathyroid hormone (PTH)–stimulated COX-2 promoter activity 40% to 60%, whereas joint mutation of NFAT and AP-1 abrogated the induction. On electrophoretic mobility shift analysis, PTH stimulated binding of phosphorylated CREB to an oligonucleotide spanning the CRE and binding of NFATc1, c-Fos, and c-Jun to an oligonucleotide spanning the NFAT/AP-1 composite site. Mutation of the NFAT site was less effective than mutation of the AP-1 site in competing binding to the composite element, suggesting that cooperative interactions of NFATc1 and AP-1 are more dependent on NFAT than on AP-1. Both PTH and forskolin, an activator of adenylyl cyclase, stimulated NFATc1 nuclear translocation. PTH- and forskolin-stimulated COX-2 promoter activity was inhibited 56% to 80% by calcium chelation or calcineurin inhibitors and 60% to 98% by protein kinase A (PKA) inhibitors. These results indicate an important role for the calcium-calcineurin-NFAT signaling pathway in the PTH induction of COX-2 and suggest that cross-talk between the cAMP/PKA pathway and the calcium-calcineurin-NFAT pathway may play a role in other functions of PTH in osteoblasts. © 2010 American Society for Bone and Mineral Research

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“…As a target of MCP-1, Akt and Erk1/2 signaling proteins are indirectly affected by Tat. Additionally, reports suggest that Tat was able to induce COX-2 and PGE2 synthesis in astroglial cells through an NFAT/AP-1-dependent mechanism [58,59]. Another interesting finding demonstrates the importance of Tat cysteine-rich domain in regulating wnt/β-catenin signaling pathway.…”

Section: Reviewmentioning

confidence: 92%

Roles and functions of HIV-1 Tat protein in the CNS: an overview

Bagashev

Sawaya

2013

Virol J

110

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Nearly 50% of HIV-infected individuals suffer from some form of HIV-associated neurocognitive disorders (HAND). HIV-1 Tat (a key HIV transactivator of transcription) protein is one of the first HIV proteins to be expressed after infection occurs and is absolutely required for the initiation of the HIV genome transcription. In addition to its canonical functions, various studies have shown the deleterious role of HIV-1 Tat in the development and progression of HAND. Within the CNS, only specific cell types can support productive viral replication (astrocytes and microglia), however Tat protein can be released form infected cells to affects HIV non-permissive cells such as neurons. Therefore, in this review, we will summarize the functions of HIV-1 Tat proteins in neural cells and its ability to promote HAND.

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Extracellular HIV-Tat Induces Cyclooxygenase-2 in Glial Cells through Activation of Nuclear Factor of Activated T Cells

Cited by 20 publications

References 75 publications

The Effect of HIV and HPV Coinfection on Cervical COX-2 Expression and Systemic Prostaglandin E2 Levels

The Effect of HIV and HPV Coinfection on Cervical COX-2 Expression and Systemic Prostaglandin E2 Levels

Parathyroid hormone induction of cyclooxygenase-2 in murine osteoblasts: Role of the calcium-calcineurin-NFAT pathway

Roles and functions of HIV-1 Tat protein in the CNS: an overview

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