Induction of C Chemokine XCL1 (Lymphotactin/Single C Motif-1α/Activation-Induced, T Cell-Derived and Chemokine-Related Cytokine) Expression by HIV-1 Tat Protein

Abstract

HIV-1 Tat has been proposed as a key agent in many AIDS-related disorders, including HIV-1-associated neurological diseases. We have recently shown that Tat expression induces a significant increase in T lymphocytes in the brains of Tat transgenic mice. The CNS infiltration of T lymphocytes has been noted in AIDS patients. In the present study using this unique genetic system we attempted to understand the underlying mechanisms of Tat expression-induced infiltration of T lymphocytes by examining chemokine expression. RNase protection assay revealed that in addition to CCL2 (monocyte chemoattractant protein-1), CCL3 (macrophage inflammatory protein-1α (MIP-1α)), CCL4 (MIP-1β), CCL5 (RANTES), CXCL2 (MIP-2), and CXCL10 (inducing protein-10), XCL1 (lymphotactin/single C motif-1α/activation-induced, T cell-derived and chemokine-related cytokine) was identified to be up-regulated by Tat expression. XCL1 is a C chemokine and plays a specific and important role in tissue-specific recruitment of T lymphocytes. Thus, we further determined the relationship between Tat and XCL1 expression. Tat-induced XCL1 expression was further confirmed by XCL1-specific RT-PCR and ELISA. Combined in situ hybridization and immunohistochemical staining identified astrocytes, monocytes, and macrophages/microglia as XCL1-producing cells in vivo. Using human astrocytes, U87.MG cells, as an in vitro model, activation of XCL1 expression was positively correlated with Tat expression. Moreover, the XCL1 promoter-driven reporter gene assay showed that Tat-induced XCL1 expression occurred at the transcriptional level. Taken together, these results demonstrate that Tat directly trans-activated XCL1 expression and suggest potential roles of Tat-induced XCL1 expression in the CNS infiltration of T lymphocytes during HIV-1 infection and subsequent HIV-1-induced neurological diseases.

Intrapulmonary Delivery of XCL1-Targeting Small Interfering RNA in Mice Chronically Infected withMycobacterium tuberculosis

“…Furthermore, the siRNA appeared to be associated with CD8 T cells and, to some extent, with CD4 T cells as well. Previous work (12,20,21,35) identified activated CD8 T cells as the main producers of XCL1 and, to some extent, natural killer and mast cell populations. We did not test for colocalization of siRNA with natural killer and mast cell populations; therefore, total suppression of xcl1 transcript might not be limited to the CD8 T-cell population.…”

Expressions of lymphotactin and its receptor, XCR, in Lewis rats with experimental autoimmune anterior uveitis

“…Previous clinical and animal studies have demonstrated that the lymphotactin-XCR interaction contributes in the pathogenesis of inflammatory diseases, including rheumatoid arthritis, systemic sclerosis, inflammatory bowel disease, glomerulonephritis and HIV infection [17][18][19][20][21][22]. In the eye, upregulation of lymphotactin expression is found in the mouse cornea after mechanical trauma or endotoxin exposure, and may be related to early corneal graft rejection [23].…”

Cannabinoid Inhibition of Macrophage Migration to the Trans-Activating (Tat) Protein of HIV-1 Is Linked to the CB2 Cannabinoid Receptor

“…HIV-1 Tat (trans-activating factor) is a regulatory protein that is indispensible for viral replication and gene expression (reviewed in Pugliese et al, 2005). This protein, once secreted, is highly immunogenic and induces the production of proinflammatory cytokines and chemokines in astrocytes (El-Hage et al, 2006), monocytes (Lafrenie et al, 1997), microglia (reviewed in Minghetti et al, 2004), and T lymphocytes (Kim et al, 2004). Tat-activated monocytes have been shown to up-regulate cell surface adhesion molecules, including vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 (Pu et al, 2003).…”