Interleukin 15: biology and relevance to human disease

Abstract

Since the cloning of interleukin (IL)-15 six years ago, there have been numerous studies examining the molecular and cellular biology of this cytokine. IL-15 and IL-2 have similar biologic properties in vitro, consistent with their shared receptor (R) signaling components (IL-2/15R␤␥ c ). However, specificity for IL-15 versus IL-2 is provided by unique private ␣-chain receptors that complete the IL-15R␣␤␥ and IL-2R␣␤␥ heterotrimeric high-affinity receptor complexes and thereby allow differential responsiveness depending on the ligand and highaffinity receptor expressed. Intriguingly, both IL-15 and IL-15R␣ transcripts have a much broader tissue distribution than IL-2/IL-2R␣. Further, multiple complex posttranscriptional regulatory mechanisms tightly control IL-15 expression. Thus, based upon complex regulation, as well as differential patterns of IL-15 and IL-15R␣ expression, it is likely that the critical in vivo functions of this receptor/ligand pair differ from those of IL-2 and IL-2R␣. Studies to date examining the biology of IL-15 have identified several key nonredundant roles, such as IL-15's importance during natural killer (NK) cell, NK-T cell, and intestinal intraepithelial lymphocyte development and function. A role for IL-15 during autoimmune processes such as rheumatoid arthritis and malignancies such as adult T-cell leukemia suggest that dysregulation of IL-15 may result in deleterious effects for the host. This review attempts to present concisely our current understanding of the cellular and molecular biology of IL-15, IL-15's role in human disease, and its potential clinical utility as a therapeutic agent or target. Molecular and cellular biology of interleukin 15 (IL-15)The discovery of IL-15 and its relation to IL-2 IL-15 was identified by 2 independent groups based upon its ability to stimulate proliferation of the IL-2-dependent CTLL-2 T-cell line in the presence of neutralizing anti-IL-2 antibodies. The activity within cell culture supernatants of the simian kidney epithelial cell line CV-1/EBNA was purified, molecularly cloned, and designated IL-15. 1 The activity identified in supernatants of the human T-cell leukemia virus-1 (HTLV-1) cell line, HuT-102, was purified and called 3 Scientists at the Immunex Corporation (Seattle, WA) isolated the 14-to 15-kd protein responsible for the CTLL proliferation within CV-1/ EBNA supernatants using anion-exchange and high-pressure liquid chromatography and sequenced the NH 2 -terminal residues. Degenerate oligonucleotide primers were generated from this partial protein sequence and were used to obtain the full-length simian IL-15 cDNA from a CV-1/EBNA cDNA library. With simian IL-15 cDNA as a probe, the full-length human IL-15 cDNA was cloned from the IMTLH bone marrow stromal cell line. 1 The IL-T protein identified by researchers at the National Institutes of Health within HuT-102 supernatants was later cloned and shown to be a chimera composed of the HTLV-1 long terminal repeat (LTR) and human IL-15. The HTLV-1 LTR was fused in frame immediatel...

IL-1β and IFN-γ induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice

“…The concentrations of IL-15 produced by human islets were low, similar to data obtained in other cell types [49,52]. It has been shown that picomolar amounts of IL-15 are effective in maintaining NK cell survival in serum-free media [49], suggesting that the observed IL-15 production by human islets might be physiologically relevant.…”

“…The main inducer of IL-15 in human islets and rat purified beta cells was IFN-γ. Similarly, IFN-γ induces IL-15 mRNA expression in monocytes and NK cells [49,50,51]. The concentrations of IL-15 produced by human islets were low, similar to data obtained in other cell types [49,52].…”

“…A constitutive expression of IL-15 was observed human islets (control), as described for kidney proximal tubule cells, astrocytes and microglia [49]. The nature of IL-15 function in non-stimulated cells requires further investigation.…”

The IL-15 cytokine system provides growth and survival signals in Hodgkin lymphoma and enhances the inflammatory phenotype of HRS cells

“…IL-15 is a pro-inflammatory cytokine that was originally identified through its ability to induce T cell proliferation, displaying IL-2-like properties. 3 Indeed, both cytokines act through a heterotrimeric receptor that shares the IL-2 receptor (IL-2R , also referred to as IL-15R , CD122) and the common chain (IL-2R , CD132).…”

“…3 Functionally, IL-15 plays a pivotal role in the differentiation and/or survival of natural killer (NK) cells, NK T cells as well as intraepithelial lymphocytes (IELs) and is critical for the maintenance of CD8 + memory T cells. 4 To identify factors that are involved in the formation of the HL-specific tumor microenvironment, we screened microarray gene expression profiles of HRS and B nonHodgkin cell lines with a special focus on cytokines and cytokine receptors.…”