Interferon-γ and tumor necrosis factor-α specifically induce formation of cytomegalovirus-permissive monocyte-derived macrophages that are refractory to the antiviral activity of these cytokines

Cecilia Söderberg-Nauclér, Kenneth N. Fish, Jay Nelson

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128 Citations (Scopus)

Abstract

Monocytes/macrophages are key cells in the pathogenesis of human cytomegalovirus (HCMV). Although HCMV infection in monocytes is restricted to early events of gene expression, productive infection has been demonstrated in differentiated macrophages in vitro. We examined the cellular and cytokine components that are essential for HCMV replication in Concanavalin A- stimulated monocyte-derived macrophages (MDM). By negative selection, depletion of CD8+ T lymphocytes, but not CD4+ T lymphocytes, CD19+ B cells, or CD56+ NK cells, resulted in a 60-70% reduction in the number of HCMV- infected MDM, and a 4 log decrease in virus production. Neutralization of IFN-γ and TNF-α, but not IL-1, IL-2, or TGF-β, decreased production of virus by 4 logs and 2 logs, respectively. Subsequently, addition of recombinant IFN-γ or TNF-α to purified monocyte cultures was sufficient to produce HCMV-permissive MDM. While IFN-γ and TNF-α possess antiviral properties, addition of these cytokines to permissive MDM cultures did not affect production of HCMV. Thus, rather than inhibiting replication of HCMV, IFN-γ and TNF-α specifically induce differentiation of monocytes into HCMV- permissive MDM, which are resistant to the antiviral effects of these cytokines.

Original languageEnglish (US)
Pages (from-to)3154-3163
Number of pages10
JournalJournal of Clinical Investigation
Volume100
Issue number12
StatePublished - Dec 15 1997

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Cytomegalovirus
Interferons
Antiviral Agents
Tumor Necrosis Factor-alpha
Macrophages
Cytokines
Monocytes
Viruses
T-Lymphocytes
Cytomegalovirus Infections
Concanavalin A
Interleukin-1
Natural Killer Cells
Interleukin-2
B-Lymphocytes
Gene Expression
Infection

Keywords

  • Cytomegalovirus
  • Differentiation
  • Interferon
  • Macrophages
  • Tumour necrosis factor

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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title = "Interferon-γ and tumor necrosis factor-α specifically induce formation of cytomegalovirus-permissive monocyte-derived macrophages that are refractory to the antiviral activity of these cytokines",
abstract = "Monocytes/macrophages are key cells in the pathogenesis of human cytomegalovirus (HCMV). Although HCMV infection in monocytes is restricted to early events of gene expression, productive infection has been demonstrated in differentiated macrophages in vitro. We examined the cellular and cytokine components that are essential for HCMV replication in Concanavalin A- stimulated monocyte-derived macrophages (MDM). By negative selection, depletion of CD8+ T lymphocytes, but not CD4+ T lymphocytes, CD19+ B cells, or CD56+ NK cells, resulted in a 60-70{\%} reduction in the number of HCMV- infected MDM, and a 4 log decrease in virus production. Neutralization of IFN-γ and TNF-α, but not IL-1, IL-2, or TGF-β, decreased production of virus by 4 logs and 2 logs, respectively. Subsequently, addition of recombinant IFN-γ or TNF-α to purified monocyte cultures was sufficient to produce HCMV-permissive MDM. While IFN-γ and TNF-α possess antiviral properties, addition of these cytokines to permissive MDM cultures did not affect production of HCMV. Thus, rather than inhibiting replication of HCMV, IFN-γ and TNF-α specifically induce differentiation of monocytes into HCMV- permissive MDM, which are resistant to the antiviral effects of these cytokines.",
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author = "Cecilia S{\"o}derberg-Naucl{\'e}r and Fish, {Kenneth N.} and Jay Nelson",
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TY - JOUR

T1 - Interferon-γ and tumor necrosis factor-α specifically induce formation of cytomegalovirus-permissive monocyte-derived macrophages that are refractory to the antiviral activity of these cytokines

AU - Söderberg-Nauclér, Cecilia

AU - Fish, Kenneth N.

AU - Nelson, Jay

PY - 1997/12/15

Y1 - 1997/12/15

N2 - Monocytes/macrophages are key cells in the pathogenesis of human cytomegalovirus (HCMV). Although HCMV infection in monocytes is restricted to early events of gene expression, productive infection has been demonstrated in differentiated macrophages in vitro. We examined the cellular and cytokine components that are essential for HCMV replication in Concanavalin A- stimulated monocyte-derived macrophages (MDM). By negative selection, depletion of CD8+ T lymphocytes, but not CD4+ T lymphocytes, CD19+ B cells, or CD56+ NK cells, resulted in a 60-70% reduction in the number of HCMV- infected MDM, and a 4 log decrease in virus production. Neutralization of IFN-γ and TNF-α, but not IL-1, IL-2, or TGF-β, decreased production of virus by 4 logs and 2 logs, respectively. Subsequently, addition of recombinant IFN-γ or TNF-α to purified monocyte cultures was sufficient to produce HCMV-permissive MDM. While IFN-γ and TNF-α possess antiviral properties, addition of these cytokines to permissive MDM cultures did not affect production of HCMV. Thus, rather than inhibiting replication of HCMV, IFN-γ and TNF-α specifically induce differentiation of monocytes into HCMV- permissive MDM, which are resistant to the antiviral effects of these cytokines.

AB - Monocytes/macrophages are key cells in the pathogenesis of human cytomegalovirus (HCMV). Although HCMV infection in monocytes is restricted to early events of gene expression, productive infection has been demonstrated in differentiated macrophages in vitro. We examined the cellular and cytokine components that are essential for HCMV replication in Concanavalin A- stimulated monocyte-derived macrophages (MDM). By negative selection, depletion of CD8+ T lymphocytes, but not CD4+ T lymphocytes, CD19+ B cells, or CD56+ NK cells, resulted in a 60-70% reduction in the number of HCMV- infected MDM, and a 4 log decrease in virus production. Neutralization of IFN-γ and TNF-α, but not IL-1, IL-2, or TGF-β, decreased production of virus by 4 logs and 2 logs, respectively. Subsequently, addition of recombinant IFN-γ or TNF-α to purified monocyte cultures was sufficient to produce HCMV-permissive MDM. While IFN-γ and TNF-α possess antiviral properties, addition of these cytokines to permissive MDM cultures did not affect production of HCMV. Thus, rather than inhibiting replication of HCMV, IFN-γ and TNF-α specifically induce differentiation of monocytes into HCMV- permissive MDM, which are resistant to the antiviral effects of these cytokines.

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KW - Differentiation

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KW - Macrophages

KW - Tumour necrosis factor

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