Disease relevance of Il15

• To investigate the role of IL-15 in psoriasis, we generated mAb's using human immunoglobulin-transgenic mice [1].
• Furthermore, mice with severe combined immunodeficiency treated with the Fab fragment of a blocking antibody recognizing a signaling subunit of the IL-15 receptor, IL-2/15Rbeta, had a significant ( approximately 90%) loss of NK cells compared with control mice [2].
• Role of interleukin 15 in colitis induced by dextran sulphate sodium in mice [3].
• IL-15 levels were elevated in the intestinal mucosa of inflammatory bowel diseases [3].
• RESULTS: IL-15 KO mice exhibited resistance to DSS induced acute colitis, as reflected by lower lethality, weight loss, clinical scores, and histological scores compared with those in control mice (p<0.05) [3].
• Our results identify an unexpected breach in MC-dependent innate immune defenses against sepsis and suggest that inhibiting intracellular IL-15 in MCs may improve survival from sepsis [4].

Psychiatry related information on Il15

• The presence of a virus-inducible region in the IL-15 promoter suggests a role for IL-15 as a component of host antiviral defense mechanisms [5].

High impact information on Il15

• Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors [6].
• T cells expanded in the presence of IL-15 uniquely persist in tumor-bearing severe combined immunodeficiency (SCID)-Beige mice and eradicate disseminated intramedullary tumors [7].
• IL-15 and IL-2: a matter of life and death for T cells in vivo [8].
• Interleukin-15 protects from lethal apoptosis in vivo [9].
• Itk(-/-) and Rlk(-/-)Itk(-/-) CD8(+) thymocytes and T cells were CD44(hi), CD122(+), and NK1.1(+); were able to produce interferon-gamma directly ex vivo; and were dependent on interleukin-15 [10].

Chemical compound and disease context of Il15

• The third subunit, the so-called common gamma (gamma c) chain, of the IL-2 receptor is shared among the receptors for IL-2, IL-4, IL-7 and IL-15, and dysfunction of the gamma c chain is thought to cause X-linked severe combined immunodeficiency (XSCID) ascribed to impairment of early T cell development [11].
• Immunoregulation during disease progression in prediabetic NOD mice: inverse expression of arginase and prostaglandin H synthase 2 vs. interleukin-15 [12].
• Impaired protection against Mycobacterium bovis bacillus Calmette-Guerin infection in IL-15-deficient mice [13].
• Increased level and longevity of protective immune responses induced by DNA vaccine expressing the HIV-1 Env glycoprotein when combined with IL-21 and IL-15 gene delivery [14].
• IL-12 or IL-15, unlike IL-2, does not interact with histamine in augmenting cytotoxicity of splenocytes against melanoma cells and YAC-1 cells [15].

Biological context of Il15

• The murine Il15 gene was found to consist of eight exons spanning at least 34 kb and was localized to the central region of mouse chromosome 8 by interspecific backcross analysis [16].
• High concentrations of IL-2 similarly induced development into NK cells, but the cell number was fourfold lower than in IL-15 cultures [17].
• Identification and cloning of a novel IL-15 binding protein that is structurally related to the alpha chain of the IL-2 receptor [18].
• Identification of a novel receptor/signal transduction pathway for IL-15/T in mast cells [19].
• IL-15 is an essential mediator of peripheral NK-cell homeostasis [20].

Anatomical context of Il15

• Interleukin (IL)-2 and IL-15 are redundant in stimulating T-cell proliferation in vitro [8].
• High concentrations of IL-15 blocked TCR alpha beta development and shifted differentiation towards NK cells [17].
• Data obtained from in situ hybridization study have suggested that the macrophages present in the pregnant uterus may be responsible for the production of IL-15 [21].
• Here, it is shown that IL-15 mRNA is mainly expressed in thymic epithelial stromal cells, whereas IL-2 mRNA is exclusively expressed in thymocytes [17].
• Here, we examine the effect of IL-15 on hyaluronan expression by endothelial cells, and investigate its role in vivo in promoting the extravasation of antigen-activated T cells through a CD44-dependent pathway [22].

Associations of Il15 with chemical compounds

• Suppressor of cytokine signaling 1 stringently regulates distinct functions of IL-7 and IL-15 in vivo during T lymphocyte development and homeostasis [23].
• Tyrosine phosphorylation data are presented showing that IL-15 signaling in microglia involves Janus kinase 1 activity [24].
• Blocking IL-15 prevents the induction of allergen-specific T cells and allergic inflammation in vivo [25].
• Treatment of IEC6 cells with IL-15 decreased doxorubicin-mediated cytotoxicity [26].
• LPS-tolerant splenocytes also exhibit decreased production of IL-15 and IL-15Ralpha [27].

Physical interactions of Il15

• The IL-15 receptor alpha subunit (IL-15Ralpha) mediates high-affinity binding of IL-15, a pleiotropic cytokine implicated in the development of innate immune cells [28].
• Nuclear protein prepared from LPS-stimulated macrophages formed a complex with the NF-kappaB binding sequence of the IL-15 promoter [29].

Regulatory relationships of Il15

• Collectively, the data support the notion that exogenous low-dose IL-15 therapy can enhance and even reverse the limited efficacy of adoptively transferred tumor-specific T-cell therapy and may do so in a fashion that is superior and distinct from exogenous IL-2 therapy [30].
• We have examined the induction of IL-15 in murine macrophages (by semiquantitative reverse transcriptase-PCR and bioassay) in response to a variety of different macrophage-activating stimuli and compared the regulation of IL-15 production to that of IL-12 and TNF-alpha [31].
• We show here the effects of IL-15 on the proliferation and maintenance of murine gamma delta i-IEL in vitro. gamma delta i-IEL constitutively expressed a high level of IL-15 receptor alpha mRNA and proliferated in response to IL-15 more vigorously than alpha beta i-IEL [32].
• Consistent with this idea, IL-15 stimulates sustained STAT5 phosphorylation in SOCS1-deficient CD8+ T cells [33].
• Although effects of IL-15 on Mphi activities have not previously been reported, its derivation from activated Mphi suggested a possible autocrine role in regulating Mphi functions and prompted us to determine whether IL-15 modulated LPS-activated Mphi cytokine production [34].

Other interactions of Il15

• Promoter analyses in a mouse macrophage cell line, RAW264.7, revealed that the 2508-bp region upstream of the transcriptional start site is sufficient for the full transcriptional activation of the IL12RB1 gene by IFN-gamma or IL-15 [35].
• These results indicate that transpresentation of IL-15 by IL-15Ralpha on BM-derived cells mediates the basal proliferation of memory CD8 T cells [36].
• Finally, NK cells from Bcl-2 transgenic mice that were adoptively transferred into IL-15(-/-) mice did survive [2].
• IL-15 selectively stimulates SOCS1-/- CD8+ thymocytes, inducing sustained signal transducer and activator of transcription 5 (STAT5) phosphorylation and massive proliferation [37].
• Moreover, IL-10, which is inhibitory for most other monokines, increased levels of IL-15 mRNA found after stimulation [31].
• IL-15-mediated inactivation of Foxo3a and cell survival were dependent on phosphotidylinositol-3-OH kinase [38].

Analytical, diagnostic and therapeutic context of Il15

• Using reverse transcription-polymerase chain reaction (RT-PCR) analysis, we have demonstrated in the present study that IL-15 and its cognate receptor, but not the other cytokines, are expressed in the mouse pregnant uterus, with a time course concomitant with those of cytolytic mediators in differentiated GMG cells [21].
• Addition of low concentrations of IL-15 to fetal thymic organ culture (FTOC) resulted in an increase of all T cell subpopulations [17].
• Resolution of psoriasis upon blockade of IL-15 biological activity in a xenograft mouse model [1].
• Using an adoptive transfer system, we have investigated the role of gammac-dependent cytokines, in particular interleukin 7 (IL-7) and IL-15, and major histocompatibility complex (MHC) class I molecules in peripheral NK-cell homeostasis [20].
• Notably, chromatin immunoprecipitation (ChIP) assays revealed IL-15 rapidly induced histone H3 acetylation at the IL12RB1 promoter [35].

References