HIV-1 transmission and cytokine-induced expression of DC-SIGN in human monocyte-derived macrophages

Abstract

Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) has been described as an attachment molecule for human immunodeficiency virus type 1 (HIV-1) with the potential to mediate its transmission. We examined DC-SIGN expression in monocyte-derived macrophages (MDM) and its role in viral transmission when MDM were exposed to interleukin (IL)-13, IL-4, or interferon-gamma (IFN-gamma). We show that IL-13 and IL-4 increase transcripts, total protein, and cell-surface expression of DC-SIGN in all MDM tested, IFN-gamma results ranged from no change to up-regulation of surface expression, and message and total protein were, respectively, induced in all and 86% of donors tested. Transmission experiments of HIV-1 X4 between cytokine-treated MDM to Sup-T1 cells showed no association between total transmission and DC-SIGN up-regulation. IL-4 but not IL-13 resulted in a less than twofold increase in MDM viral transmission to CD4+ T cells in spite of a fourfold up-regulation in DC-SIGN expression by either cytokine. In contrast, IFN-gamma treatment induced a decrease in total transmission by at least two-thirds, despite its induction of DC-SIGN. Soluble mannan resulted in a greater inhibition of viral transmission to CD4+ T cells than neutralizing anti-DC-SIGN monoclonal antibody (67-75% vs. 39-48%), supporting the role of mannose-binding receptors in viral transmission. Taken together, results show that DC-SIGN regulation in MDM does not singly predict the transmission potential of this cell type.

Regulated Expression of the Pathogen Receptor Dendritic Cell-specific Intercellular Adhesion Molecule 3 (ICAM-3)-grabbing Nonintegrin in THP-1 Human Leukemic Cells, Monocytes, and Macrophages

“…Our results (Ref. 18 and this report) and those of others (3,4,37) indicate that IL-4 induces DC-SIGN expression on monocytes and monocyte-derived macrophages and is the key cytokine for DC-SIGN acquisition during monocyte-derived dendritic cell differentiation (18). The differential expression of DC-SIGN in differentiated THP-1 in the absence (DC-SIGN dull ) or presence of IL-4 (DC-SIGN high ) further illustrates the impact of IL-4 on myeloid cell differentiation and demonstrates the IL-4 dependence of the DC-SIGN expression in both normal and transformed myeloid cells.…”

Dendritic Cell-Specific Intercellular Adhesion Molecule 3-Grabbing Nonintegrin/CD209 Is Abundant on Macrophages in the Normal Human Lymph Node and Is Not Required for Dendritic Cell Stimulation of the Mixed Leukocyte Reaction

“…It is possible that the equivalent of the cultured monocyte-derived DCs only develops under select circumstances, e.g., during an inflammatory response or in special tissue niches. We and others (19,31,37,39) found that cytokines such as IL-4, IL-13, and IL-15 quickly up-regulated DC-SIGN expression on monocytes, so that cells with the phenotype of monocyte-derived DCs might accumulate in situations such as parasite infection and allergy. The reports of DC-SIGN ϩ cells in lymphatic sinuses, particularly in the subcapsular region of lymph nodes, may also reflect migratory monocyte-derived DCs responding to a stimulus in the periphery.…”

Dysregulation of TLR3 Impairs the Innate Immune Response to West Nile Virus in the Elderly

“…DC-SIGN is a CLR described in the binding and transmission of human immunodeficiency virus type 1 (5,11) and mediates cell responses via downstream kinase signaling (4). Consistent with an earlier report (4), we found that Lyn, an Src family kinase, was recruited after DC-SIGN ligated with the glycosylated WNV-E protein and that ligation of DC-SIGN increased the phosphorylation of Lyn at the carboxyl terminus, while the phosphorylation at the activation loop of Lyn was unaffected.…”