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

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 secret ion is only found exceptionally, eg, conditions of pathological, chronic in flammation. This raises the possibility that monocytes express membrane-bou nd IL-15 rather than secrete it. The current study explores this hypothesis . We demonstrate here that biologically active IL-15 is indeed detectable i n 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-Ba rr virus-immortalized B-cell clones). Furthermore, cell surface-bound IL-15 is upregulated upon interferon-gamma 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-b ound IL-15 does not elute with acetate buffer or trypsin treatment, suggest ing that it is an integral membrane protein and that it is not associated w ith the IL-15 receptor complex. Finally, membrane-bound IL-15 stimulates T lymphocytes to proliferate in vitro, indicating that it is biologically act ive. These findings enlist IL-15 in the fairly small family of cytokines fo r which the presence of a biologically active membrane-bound form has been demonstrated leg, IL-1, tumor necrosis factor-alpha, and IL-10) and invites the speculation that most of the biological effects of IL-15 under physiol ogical conditions are exerted by the cell surface-bound form. (C) 1999 by T he American Society of Hematology.