Human monocytes constitutively express membrane-bound, biologically active, and interferon-γ-upregulated interleukin-15

Tiziana Musso, Liliana Calosso, Mario Zucca, Maura Millesimo, Daniela Ravarino, Mirella Giovarelli, Fabio Malavasi, Alessandro Negro Ponzi, Ralf Paus, Silvia Bulfone-Paus

Research output: Contribution to journalArticle

180 Citations (Scopus)

Abstract

Interleukin-15 (IL-15) is a potent regulator of T-, B-, and natural killer cell proliferation and displays unusually tight controls of secretion. Even though IL-15 mRNA is constitutively expressed in monocytes/macrophages and is upregulated by a variety of stimuli, evidence for IL-15 cytokine secretion is only found exceptionally, eg, conditions of pathological, chronic inflammation. This raises the possibility that monocytes express membrane-bound IL-15 rather than secrete it. The current study explores this hypothesis. We demonstrate here that biologically active IL-15 is indeed detectable in a constitutively expressed, membrane-bound form on normal human monocytes, as well as on monocytic cell lines (MONO-MAC-6, THP-1, and U937), but not on human T or B cells (MT4, M9, C5966, JURKAT, DAUDI, RAJI, and Epstein-Barr virus-immortalized B-cell clones). Furthermore, cell surface- bound IL-15 is upregulated upon interferon-γ stimulation. Interestingly, monocyte/macrophage inhibitory cytokines such as IL-4 and IL-13 fail to downregulate both constitutive and induced cell-surface expression of IL-15. Membrane-bound IL-15 does not elute with acetate buffer or trypsin treatment, suggesting that it is an integral membrane protein and that it is not associated with the IL-15 receptor complex. Finally, membrane-bound IL-15 stimulates T lymphocytes to proliferate in vitro, indicating that it is biologically active. These findings enlist IL-15 in the fairly small family of cytokines for which the presence of a biologically active membrane-bound form has been demonstrated (eg, IL-1, tumor necrosis factor-α, and IL-10) and invites the speculation that most of the biological effects of IL-15 under physiological conditions are exerted by the cell surface-bound form.

Original languageEnglish (US)
Pages (from-to)3531-3539
Number of pages9
JournalBlood
Volume93
Issue number10
StatePublished - May 15 1999
Externally publishedYes

Fingerprint

Interleukin-15
Interferons
Monocytes
Membranes
Macrophages
Cytokines
Interleukin-15 Receptors
Clone cells
B-Lymphocytes
Cells
T-Lymphocytes
T-cells
Interleukin-13
Cell proliferation
Human Herpesvirus 4
Interleukin-1
Viruses
Interleukin-4
Interleukin-10
Trypsin

ASJC Scopus subject areas

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

Cite this

Musso, T., Calosso, L., Zucca, M., Millesimo, M., Ravarino, D., Giovarelli, M., ... Bulfone-Paus, S. (1999). Human monocytes constitutively express membrane-bound, biologically active, and interferon-γ-upregulated interleukin-15. Blood, 93(10), 3531-3539.

Human monocytes constitutively express membrane-bound, biologically active, and interferon-γ-upregulated interleukin-15. / Musso, Tiziana; Calosso, Liliana; Zucca, Mario; Millesimo, Maura; Ravarino, Daniela; Giovarelli, Mirella; Malavasi, Fabio; Negro Ponzi, Alessandro; Paus, Ralf; Bulfone-Paus, Silvia.

In: Blood, Vol. 93, No. 10, 15.05.1999, p. 3531-3539.

Research output: Contribution to journalArticle

Musso, T, Calosso, L, Zucca, M, Millesimo, M, Ravarino, D, Giovarelli, M, Malavasi, F, Negro Ponzi, A, Paus, R & Bulfone-Paus, S 1999, 'Human monocytes constitutively express membrane-bound, biologically active, and interferon-γ-upregulated interleukin-15', Blood, vol. 93, no. 10, pp. 3531-3539.
Musso T, Calosso L, Zucca M, Millesimo M, Ravarino D, Giovarelli M et al. Human monocytes constitutively express membrane-bound, biologically active, and interferon-γ-upregulated interleukin-15. Blood. 1999 May 15;93(10):3531-3539.
Musso, Tiziana ; Calosso, Liliana ; Zucca, Mario ; Millesimo, Maura ; Ravarino, Daniela ; Giovarelli, Mirella ; Malavasi, Fabio ; Negro Ponzi, Alessandro ; Paus, Ralf ; Bulfone-Paus, Silvia. / Human monocytes constitutively express membrane-bound, biologically active, and interferon-γ-upregulated interleukin-15. In: Blood. 1999 ; Vol. 93, No. 10. pp. 3531-3539.
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abstract = "Interleukin-15 (IL-15) is a potent regulator of T-, B-, and natural killer cell proliferation and displays unusually tight controls of secretion. Even though IL-15 mRNA is constitutively expressed in monocytes/macrophages and is upregulated by a variety of stimuli, evidence for IL-15 cytokine secretion is only found exceptionally, eg, conditions of pathological, chronic inflammation. This raises the possibility that monocytes express membrane-bound IL-15 rather than secrete it. The current study explores this hypothesis. We demonstrate here that biologically active IL-15 is indeed detectable in a constitutively expressed, membrane-bound form on normal human monocytes, as well as on monocytic cell lines (MONO-MAC-6, THP-1, and U937), but not on human T or B cells (MT4, M9, C5966, JURKAT, DAUDI, RAJI, and Epstein-Barr virus-immortalized B-cell clones). Furthermore, cell surface- bound IL-15 is upregulated upon interferon-γ stimulation. Interestingly, monocyte/macrophage inhibitory cytokines such as IL-4 and IL-13 fail to downregulate both constitutive and induced cell-surface expression of IL-15. Membrane-bound IL-15 does not elute with acetate buffer or trypsin treatment, suggesting that it is an integral membrane protein and that it is not associated with the IL-15 receptor complex. Finally, membrane-bound IL-15 stimulates T lymphocytes to proliferate in vitro, indicating that it is biologically active. These findings enlist IL-15 in the fairly small family of cytokines for which the presence of a biologically active membrane-bound form has been demonstrated (eg, IL-1, tumor necrosis factor-α, and IL-10) and invites the speculation that most of the biological effects of IL-15 under physiological conditions are exerted by the cell surface-bound form.",
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AU - Ravarino, Daniela

AU - Giovarelli, Mirella

AU - Malavasi, Fabio

AU - Negro Ponzi, Alessandro

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