Lipopolysaccharide-Stimulated or Granulocyte-Macrophage Colony-Stimulating Factor-Stimulated Monocytes Rapidly Express Biologically Active IL-15 on Their Cell Surface Independent of New Protein Synthesis

Abstract

Although IL-15 shares many of the biological activities of IL-2, IL-2 expression is primarily under transcriptional regulation, while the mechanisms involved in the regulation of IL-15 are complex and not completely understood. In the current study, we found that CD14+ monocytes constitutively exhibit both IL-15 mRNA and protein. IL-15 protein was found stored intracellularly and stimulation of CD14+ monocytes with either LPS or GM-CSF resulted in mobilization of IL-15 stores to the plasma membrane. This rapidly induced surface expression was the result of a translocation of preformed stores, confirming that posttranslational regulatory stages limit IL-15, because it was not accompanied by an increase in IL-15 mRNA and occurred independent of de novo protein synthesis. After fixation, activated monocytes, but not resting monocytes, were found to support T cell proliferation, and this effect was abrogated by the addition of an IL-15-neutralizing Ab. The presence of preformed IL-15 stores and the ability of stimulated monocytes to mobilize these stores to their surface in an active form is a novel mechanism of regulation for IL-15.

Endogenous IL-15 Sustains Recruitment of IL-2Rβ and Common γ and IL-2-Mediated Chemokine Production in Normal and Inflamed Human Gingival Fibroblasts

“…3, C and D). This observation suggests that translation or intracellular trafficking of IL-15 in HGF is regulated, which is in agreement with recent reports showing that IL-15 is constitutively expressed on fibroblasts from human spleen and skin and also on human monocytes and leukemic progenitors without any IL-15 secretion (22)(23)(24)(25)(26). Considering these findings, it is conceivable that HGF express endogenous IL-15 as the membranebound IL-15, which is the transcript encoding 48 aa-IL-15.…”

“…The 48 aa-IL-15 is targeted to the secretory pathway with low secretion potential (19,20), whereas the 21 aa-IL-15 appears to be restricted to the cytoplasm and nucleus (19,21). Recent reports showed that IL-15 is constitutively expressed on fibroblasts from human spleen and skin and also on human monocytes and leukemic progenitors without any IL-15 secretion (22)(23)(24)(25)(26). However, it is still unclear which of the isoforms are expressed on the cell surface.…”

Follicular Dendritic Cells Produce IL-15 That Enhances Germinal Center B Cell Proliferation in Membrane-Bound Form

“…It is also possible that detection is difficult because IL-15 is usually bound to IL-15R␣. The membrane form is known to be biologically active, more potent than the soluble form (52,66). The bioactivity of IL-15 on the FDC surface was also demonstrated by the CTLL-2 assay.…”

“…The presence of membrane-bound IL-15 on FDCs in place of secreted protein is not uncommon. Various cell types, such as monocytes, fibroblasts, epithelial cells, and leukemic progenitors, have been reported to express membrane-bound IL-15 in the absence of detectable soluble protein (52,(65)(66)(67). In fact, IL-15 protein is rarely detected in culture supernatant or in tissues (68), due in part to the poor translation and short half-life of the cytokine.…”

Fibroblasts from Human Spleen Regulate NK Cell Differentiation from Blood CD34+ Progenitors Via Cell Surface IL-15

“…In contrast, blood-derived cells, including monocytes, monoblastoid cells, and leukemic progenitors, have been reported to constitutively express membrane-associated IL-15 without any IL-15 secretion (27)(28)(29). This membrane form has been proposed to be the bioactive form of IL-15 (27) and the result of IL-15 mobilization from intracellular stores to the membrane (30). Unlike resting and stimulated cells, secreted rather than unsecreted bound IL-15 was detected on the surface of splenic fibroblasts.…”