Disease relevance of IL15

• These results provide evidence for an association of spontaneous regression with increased transcript levels for the cytokine combination GM-CSF, IL2, and IL15 in malignant melanoma [1].
• Expansion of EBV latent membrane protein 2a specific cytotoxic T cells for the adoptive immunotherapy of EBV latency type 2 malignancies: influence of recombinant IL12 and IL15 [2].
• Abnormalities of IL-15 expression have been described in patients with rheumatoid arthritis or inflammatory bowel disease and in diseases associated with the retroviruses HIV and HTLV-I [3].
• Interleukin-15 is an autocrine/paracrine viability factor for cutaneous T-cell lymphoma cells [4].
• Defective expression of the interleukin-2/interleukin-15 receptor beta subunit leads to a natural killer cell-deficient form of severe combined immunodeficiency [5].
• HSC activation levels positively correlated with peripheral CD4+ and CD8+ T cell immune activation and were associated with enhanced interleukin-15 (IL-15) gene expression, suggesting a pathogenic role for IL-15-driven immunomediated hepatic fibrosis [6].

Psychiatry related information on IL15

• The evidence that IL-15 upregulates the expression of coligands that favor the contact between T cells and APC, per se, triggers T-cell activation and proliferation and acts as a chemoattractant for T cells, suggests that IL-15 plays a key role in Tc1-mediated defense mechanisms taking place in extravascular tissues of patients with HIV disease [7].
• It is proposed that this codependence between IL-12 and IL-15 for the activation of inflammatory T cells may be involved in chronic inflammatory disorders that are dominated by a Th1 response [8].
• Our findings suggest that interleukin-15 may be implicated in the pathophysiology of Alzheimer's disease and frontotemporal dementia [9].
• Our results demonstrate that undifferentiated HM were highly resistant to HHV-6 infection, whereas HM pretreated with human recombinant IL-15 showed an increased permissiveness for HHV-6 infection [10].

High impact information on IL15

• Furthermore, following IM, expression of the receptor for the homeostatic cytokine IL-15 on NK and T cells is lost within these individuals [11].
• IL-2, IL-15, and IL-7 are cytokines that are critical for regulating lymphoid homeostasis [12].
• IL-2 is necessary to destroy self-reactive lymphocytes and thus favors peripheral tolerance to self-antigens, whereas IL-15 favors the persistence of lymphocytes involved in the memory and effector responses to invading pathogens but risks the development of inflammatory autoimmune diseases [13].
• The multifaceted regulation of interleukin-15 expression and the role of this cytokine in NK cell differentiation and host response to intracellular pathogens [3].
• Mast cells respond to IL-15 with a receptor system that does not share elements with the IL-2 receptor but uses a novel 60- to 65-kDa IL-15RX subunit [3].

Chemical compound and disease context of IL15

• Using cell culture techniques, reverse transcriptase-polymerase chain reaction (RT-PCR), and immunhistochemistry we found that IL-15, like IL-7, is a growth factor for the Sézary cell line SeAx and that both cytokines prolonged the survival of malignant T cells directly isolated from Sézary syndrome (SS) patients [4].
• The constitutive expression of high levels of IL-15 mRNA was observed in all the cell lines examined, including Y79 retinoblastoma, IMR-32 neuroblastoma, SK-N-SH neuroblastoma, U-373MG glioma, KG-1-C glioma, NTera2 teratocarcinoma and neurons derived from NTera2 cells following treatment with retinoic acid (RA) [14].
• Interestingly, synovial fluid cells, in contrast to PBMCs isolated from patients with rheumatoid arthritis, but not osteoarthritis, respond to PMA + ionomycin with much lower, comparable to IL-15-triggered IL-17 secretion [15].
• Histological characteristics and altered expression of interleukins (IL) IL-13 and IL-15 in endometria of levonorgestrel users with different uterine bleeding patterns [16].
• Mucosal Inflammation in Celiac Disease: Interleukin-15 Meets Transforming Growth Factor beta-1 [17].

Biological context of IL15

• Monokines IL12, IL15, and IL18 have been shown to activate NK cell function, however with high apoptosis induced by their combination within 48 h [18].
• One isoform has a shorter putative signal peptide (21 amino acids) and its transcript shows a tissue distribution pattern that is distinct from that of the alternative IL-15 isoform with a 48-aa signal peptide [19].
• Our results show that IL-15 stimulates cell proliferation and cytotoxic activity of GL in LDGL patients [20].
• Interleukin-7 (IL-7) and IL-15 have been recently identified as growth factors for cutaneous T-cell lymphoma (CTCL) cells, and they protect these cells from cell death [21].
• The reduced production of IL-15 from activated CB may contribute to the immaturity of CB cellular immunity and delayed immune reconstitution after unrelated CB transplantation [22].

Anatomical context of IL15

• These findings may not only explain previous reports of transformation of CTL into NK-like "lymphokine-activated killers" (LAK cells) under high doses of IL2 (a substitute for IL15) but may also have significant implications for understanding and treating immunopathological diseases [23].
• In a phase I-II clinical trial, HuMax-IL15 was well tolerated clinically, with no significant effects on T lymphocyte subset and natural killer cell numbers [24].
• Furthermore, we show that TEC-derived soluble factors inhibit generation of NK-CFU and inhibit IL15- or IL2-driven NK cell differentiation from thymic CD34(+) triple-negative thymocytes [25].
• METHODS: Mononuclear cells from blood and synovial fluid (SF) of RA patients were isolated and cultured in vitro under experimental conditions involving the addition of HuMax-IL15 [24].
• The increase in IL15 correlated with the increase in TNFalpha (r(s)=0.66, p<0.01); however it did not correlate with the levels of erythrocyte sedimentation rate and C reactive protein, suggesting that IL15 may not be a useful marker in estimating the severity of inflammation in KD [26].

Associations of IL15 with chemical compounds

• The analysis of patient Sézary cells and three CTCL cell lines by RT-PCR showed that all these cells expressed IL-15 mRNA, but only a few (25%) produced IL-7 mRNA [4].
• Lipopolysaccharide (LPS)-stimulated CB and APB MNCs were used to determine IL-15 expression and protein production by Northern analysis and Western immunoblot analysis [22].
• IL-15 stimulated the proliferation of freshly isolated leukemic B cells, but not resting normal B lymphocytes, the latter being able to grow in the presence of IL-15 only after in vitro preactivation with phorbol myristate acetate [27].
• IL-7 and IL-15 also supported the growth of SeAx cells in the presence of the apoptosis inducing agents dexamethasone and retinoic acid [4].
• Conversely, in CB progenitors, anti-IL-15 mAb inhibited VCAM-1 and beta1 integrin expression without affecting gammac chain expression and, most important, up-regulated SDF-1 expression [28].

Physical interactions of IL15

• We conclude that normal and T84 colonic epithelial cells express IL-15R alpha and are able to bind IL-15 [29].
• IL-15 interacts with components of the IL-2 receptor and exhibits T-cell stimulating activity similar to that of IL-2 [30].
• In this study, we further report that short-time incubation of NK lymphocytes with IL-15 converts the membrane-bound CD160 to a soluble form through a proteolytic cleavage involving a metalloprotease [31].
• The NKG2D receptor costimulates effector/memory CD8 T cells and is normally absent on CD4 T cells but can be induced by T cell antigen receptor complex stimulation and interleukin-15 (IL-15) [32].
• DNA fragmentation and Annexin V binding accompanied by UVB-induced apoptosis were reduced by 30-50% with IL-15 [33].

Regulatory relationships of IL15

• Peripheral blood (PB) T cells activated by IL-15 induced significant TNF-alpha production by macrophages via a cell-contact-dependent mechanism [34].
• IL-15 induced a significant T-cell proliferation and upregulated CD25 expression [35].
• Interleukin-15 up-regulates interleukin-2 receptor alpha chain but down-regulates its own high-affinity binding sites on human T and B cells [36].
• Interleukin-15 differentially enhances the expression of interferon-gamma and interleukin-4 in activated human (CD4+) T lymphocytes [37].
• It has been reported that IL-18-induced cytokine production may be significantly enhanced by coincident addition of IL-15 [38].

Other interactions of IL15

• Interleukin 15 (IL-15) is a novel cytokine with interleukin-2-like activity [39].
• Interleukin-15 mediates T cell-dependent regulation of tumor necrosis factor-alpha production in rheumatoid arthritis [34].
• These observations identify the STAT proteins activated by IL-2 and IL-15 and therefore define signaling pathways by which these T-cell growth factors may regulate gene transcription [40].
• Constitutive and interleukin-7/interleukin-15 stimulated DNA binding of Myc, Jun, and novel Myc-like proteins in cutaneous T-cell lymphoma cells [41].
• The role of interleukin-10 (IL-10) in IL-15-mediated T-cell responses [35].

Analytical, diagnostic and therapeutic context of IL15

• In conclusion, short-term exposure of CD56+ cells to IL15/IL12 or IL15/IL18 at 8-day intervals may hold a promise for improved clinical results in cellular adoptive cancer immunotherapy and for the in vivo injections of the monokines [18].
• We report the presence of high concentrations of IL-15 in rheumatoid arthritis (RA) synovial fluid and have demonstrated its expression in the synovial membrane lining layer by immunohistochemistry [39].
• But IL-15 did not alter the number of natural killer cells, as determined by quantitating CD16 and CD56 by immunofluorescence [42].
• Secretion of IL-8 and MCP-1 proteins is detectable by enzyme-linked immunosorbent assay as early as 6 hours after stimulation with IL-15 [43].
• Using RT-PCR analysis, we demonstrated that highly purified CD3+ and CD3- GL did not express mRNA for IL-15 or IL-2 [20].

References