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Blood, Vol. 93 No. 10 (May 15), 1999:
pp. 3531-3539
Human Monocytes Constitutively Express Membrane-Bound, Biologically
Active, and Interferon- -Upregulated Interleukin-15
Tiziana Musso,
Liliana Calosso,
Mario Zucca,
Maura Millesimo,
Daniela Ravarino,
Mirella Giovarelli,
Fabio Malavasi,
Alessandro Negro Ponzi,
Ralf Paus, and
Silvia Bulfone-Paus
From the Department of Public Health and Microbiology, Postgraduate
School of Clinical Pathology, Department of Genetics, Biology and
Medical Chemistry, and Department of Clinical and Biological Sciences,
University of Turin, Turin, Italy; the Institute of Biology and
Genetics, University of Ancona, Ancona, Italy; the Department of
Dermatology, Charité, Humboldt University, Berlin, Germany; and
the Institute for Immunology, University Hospital Benjamin Franklin,
Free University Berlin, Berlin, Germany.
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-
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- , 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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