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 Scopus citations

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

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    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, 93(10), 3531-3539.