Interleukin15 221 Basic Biology

IL-15 was simultaneously described by Grabstein et al. and by Waldmann et al. in 1994. IL-15 (14-15 kDa) is a 4-a helix cytokine with structural similarities to IL-2 (Grabstein et al. 1994; Bamford et al. 1994). IL-15 mRNA is found in numerous normal human tissues and cell types, including activated monocytes, dendritic cells and fibrob-lasts (reviewed in Waldmann et al. 1999). Protein expression is more restricted, reflecting tight regulatory control of translation and secretion. IL-15 is subject to significant post-transcriptional regulation via 5'UTR AUG triplets, 3' regulatory elements and a further putative C-terminus region regulatory site. Two isoforms of IL-15 with altered glycosylation are described - a long signalling peptide form (48-aa), which is secreted from the cell, and a short signalling peptide (21-aa) form, which remains intracellular, localised to nonendoplasmic regions in both cytoplasmic and nuclear compartments (Waldmann et al. 1999). Cell membrane expression may be crucial in mediating extracellular function rather than secretion and in part explains the difficulty in detecting soluble IL-15 in biologic systems.

IL-15 functions via a widely distributed heterotrimeric receptor (IL-15R) that consists of a P-chain (shared with IL-2) and common y-chain, together with a unique a-chain (IL-15a) that in turn exists in eight isoforms (Waldmann 1999). This structure-function relationship has now been defined - IL-15 binds IL-15Ra via regions in the B helix and the C helix. A further region in the D-helix is involved in function but not a chain binding and presumably accounts for Py chain interactions (Bernard et al. 2004). Of interest peptides generated in these studies offer potent inhibitory and agonistic IL-15 modulatory potential. The IL-15 receptor complex may form in cis or trans orientation allowing for receptor component sharing between adjacent cells (Dubois et al. 2002). Like IL-2, the IL-15RaPy complex signals through JAK1/3 and STAT3/5 (Giri et al. 1995; Waldmann et al. 1998). Additional signalling through src-related tyrosine kinases and Ras/Raf/MAPK to fos/jun activation is also proposed. High affinity (10nM-1) with slow off-rate makes IL-15Ra in soluble form a useful and specific inhibitor in biologic systems. Recently, a native soluble IL-15Ra has been identified that is present in plasma and is generated via proteolytic cleavage of membrane-expressed IL-15Ra by a matrix metalloproteinase (Mortier et al. 2004). Such cleavage occurs in part through activity of TACE (Budagian et al. 1994a). The natural sIL-15Ra has high affinity for native IL-15, and is capable of inhibiting IL-15 binding to membrane receptor, preventing effector cell function including proliferation. Whether such soluble IL-15Ra can contribute to receptor complex formation is unclear at this time.

Several intriguing recent observations suggest that IL-15 can function as a signalling molecule itself. Thus, membrane IL-15 exists as a membrane-bound moiety that is not dependent upon the presence of IL-15Ra. Such IL-15 was capable of promoting cytokine release in monocytes (Budagian et al. 2004b) and increased monocyte adhesion via the small molecular weight Rho-GTPase Rac3 (Neely et al. 2004). Several data suggest involvement also of MAPK pathways including erk1/2 and p38. Intriguing parallel analysis of the structure of IL-15LSP with TNFa reveals striking similarities in the presence of predicted transmembrane and cytoplasmic domains for both cytokines, suggesting that functional relationships for IL-15 may lie closer to TNFa than IL-2 (Budagian et al. 2004b).

2.2.2 Immunologic Activities of IL-15

Commensurate with the broad expression of IL-15R, diverse pro-inflammatory activities have been attributed to IL-15. Effects on natural killer (NK) and T cells are most prominent. IL-15 induces proliferation of mitogen-activated CD4+ and CD8+ T cells, T-cell clones and yS T cells, with release of soluble IL-2Ra, and enhances cytotoxicity both in CD8+ T cells and lymphokine-activated killer cells (Grabstein et al. 1994; Bamford et al. 1994; Nishimura et al. 1996: Treiber-Held et al. 1996). CD69 expression is upregulated on CD45RO+ but not CD45RA+ T-cell subsets, consistent with the distribution of IL-2RP expression (Kanegane and Tosato 1996). IL-15 also induces NK cell activation, measured either by direct cytotoxicity, antibody-dependent cellular cytotoxicity or production of cytokines. It has been directly implicated in promoting NK cell mediated shock in mice. Moreover, IL-15 is implicated in thymic development of T cell and, particularly, NK cell lineages. IL-15 likely also functions as an NK cell survival factor in vivo by maintaining Bcl-2 expression (reviewed by Fehniger and Caligiuri 2001).

IL-15 exhibits T-cell chemokinetic activity and induces adhesion molecule (e.g. intercellular adhesion molecule [ICAM]-3) redistribution (Wilkinson and Liew 1995; Nieto et al. 1996). It further induces chemokine (CC-, CXC- and C-type) and chemokine receptor (CC but not CXC) expression on T cells (Perera and Waldmann 1999). Thus, IL-15 can recruit T cells and, thereafter, modify homo- or heterotypic cell-cell interactions within inflammatory sites. Whether IL-15 prejudices T helper 1 (Th1) or Th2 differentiation in addition to recruitment is controversial. IL-15 primes naive CD4+ T cells from TCR-transgenic mice for subsequent IFNy expression, but not IL-4 production (Seder 1996). Antigen-specific responses in T cells from human immunod eficiency virus-infected patients in the presence of high-dose IL-15 exhibit increased IFNy production, particularly if IL-12 is relatively deficient (Seder et al. 1995). Similarly, IL-15 induces IFNy/IL-4 ratios which favour Th1 dominance in mitogen-stimulated human T cells. However, IL-15 induces IL-5 production from allergen-specific human T-cell clones, implying a positive role in Th2-mediated allergic responses (Mori et al. 1996). Moreover, administration of soluble IL-15-IgG2b fusion protein in murine hypersensitivity models clearly implicates IL-15 in Th2 lesion development (Ruckert et al. 1998). Thus, through its function as a T-cell growth factor, IL-15 can probably sustain either Th1 or Th2 polarisation.

IL-15 mediates potent effects beyond T/NK cell biology. It promotes B-cell proliferation and immunoglobulin synthesis in vitro, in combination either with CD40 ligand (CD40L), or immobilised anti-IgM (Armitage et al. 1995). IL-15 has also been proposed as an autocrine regulator of macrophage activation, such that low levels of IL-15 suppress, whereas higher levels enhance pro-inflammatory monokine production (Alleva et al. 1997). Moreover, since human macrophages constitutively express bioactive membrane-bound IL-15, such autocrine effects are likely of early importance during macrophage activation (Musso et al. 1999). Similarly, neutrophils express IL-15Ra, and IL-15 can induce neutrophil activation, cytoskeletal rearrangement and protection from apoptosis (Girard et al. 1998). IL-15 has been proposed to promote angiogenesis and amplify fibroblast function via reversal of apoptosis. Finally, addition of IL-15 to rat bone marrow cultures induces osteoclast development and upregulates calcitonin receptor expression (Ogata et al. 1999).

IL-15 apparently represents a mechanism whereby host tissues can contribute to the early phase of immune responses, providing enhancement of polymorphonuclear and NK-cell responses, and subsequently T-cell responses, prior to optimal IL-2 production. The corollary to such pleiotropic activity may be a propensity to chronic, rather than self-limiting, inflammation should IL-15 synthesis be aberrantly regulated.

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