Association between single nucleotide polymorphism of IL15RA gene with susceptibility to ossification of the posterior longitudinal ligament of the spine.

BACKGROUND: Previous studies reported the association between single nucleotide polymorphism (SNP) of IL15 receptor alpha (IL15RA) gene with susceptibility to ossification of the posterior longitudinal ligament of the spine (OPLL). However, the results were still in controversy. Therefore, the purpose of the present study was to investigate the association between SNPs of IL15RA gene with susceptibility to OPLL in a Chinese Han population. METHODS: A total of 235 OPLL patients and 250 age-matched healthy controls were recruited. All the subjects were genotyped using the PCR (polymerase chain reaction)-based invader assay. A case-control study was performed to define the contribution of rs2228059 and rs2296139 to predisposition of OPLL. We also performed subgroup analysis according to the different gender. RESULTS: A significant association of rs2228059 with OPLL was observed in the Chinese Han population (p <0.001, OR = 1.63, 95% CI = 1.26-2.11). The subgroup analysis showed that there was a significant association between the allele frequency of rs2228059 and the susceptibility of OPLL in males (p = 0.002, OR = 1.72, 95% CI = 1.23-2.42). However, there was no significant association between SNP of rs2296139 and susceptibility to OPLL. CONCLUSIONS: The present study demonstrates that the SNP of rs2228059 in IL15RA gene is associated with susceptibility to OPLL in a Chinese Han population, especially in males.

Interleukin-15 affects serotonin system and exerts antidepressive effects through IL15Rα receptor.

Contrary to the reduction of depressive-like behavior observed in several strains of cytokine receptor knockout mice, mice lacking the specific receptor for interleukin (IL)-15 showed increased immobility in tail suspension and modified forced swimming tests. There was also a reduction in social interactions. The hippocampus of the IL15Rα knockout mice had decreased mRNA for 5-HT(1A), increased mRNA for 5-HT(2C), and region-specific changes of serotonin reuptake transporter (SERT) immunoreactivity. Fluoxetine (the classic antidepressant Prozac, which inhibits 5-HT(2C) and SERT) reduced the immobility of the IL15Rα knockout mice in comparison with their pretreatment baseline. Together with the unchanged performance of the IL15Rα knockout mice on the rotarod, this response to fluoxetine indicates that the immobility reflects depression. Wildtype mice responded to IL15 treatment with improvement of immobility induced by forced swimming, whereas the knockout mice failed to respond. Thus, the cognate IL15 receptor is necessary for the antidepressive activity of IL15. In ex vivo studies, IL15 decreased synaptosomal uptake of 5-HT, and modulated the expression of 5-HT(2C) and SERT in cultured neurons in a dose- and time-dependent manner. Thus, the effect of IL15 on serotonin transmission may underlie the depressive-like behavior of IL15Rα knockout mice. We speculate that IL15 is essential to maintain neurochemical homeostasis and thereby plays a role in preventing neuropsychiatric symptoms.

Essential role of interleukin-15 receptor in normal anxiety behavior.

The interactions between the cytokine interleukin (IL)-15 and the classical neurotransmitter GABA have been shown in IL15Rα receptor knockout mice by observations of memory deficits and reduction of GABA. To test the hypothesis that IL15 affects anxiety-like behavior, knockout mice without IL15, IL15Rα, or the co-receptor IL2Rγ were subjected to open-field and elevated plus maze tests. All three strains showed reduction of anxiety, with greater changes in the IL15Rα knockout mice than in the IL15 or IL2Rγ knockout mice. This unexpected observation is opposite to the reported increase of anxiety in mice lacking other proinflammatory cytokines or their receptors. The reduced anxiety was not associated with changes in associated serum cytokines. However, Western blotting, qPCR, and immunohistochemistry all showed that IL15Rα knockout mice had mild microgliosis and astrogliosis in the hippocampus. To determine whether this gliosis plays a role in decreasing anxiety, IL15Rα knockout mice were treated with minocycline, but this did not cause a change in open field performance. To determine whether IL15 plays a direct role in anxiety, wildtype mice were treated with IL15 by intraperitoneal injection. This also failed to cause a change in open field behavior under the experimental conditions tested. Thus, IL15Rα is essential for normal anxiety-like behavior, but inhibition of gliosis in the fearless IL15Rα knockout mice or IL15 treatment of normal mice did not acutely modulate behavioral performance as tested.

Cerebral interleukin-15 shows upregulation and beneficial effects in experimental autoimmune encephalomyelitis.

Interleukin (IL)-15 can cross the blood-brain barrier to act on its specific brain receptor (IL15Ralpha) and co-receptors. The important roles of neuronal IL15 and IL15Ralpha in experimental autoimmune encephalomeylitis (EAE) are suggested by the upregulation of IL15Ralpha mRNA in different regions of the brain and spinal cord, and by double-labeling immunohistochemistry showing neuronal localization of IL15 and IL15Ralpha in different neurons. Contrary to expectations, IL15 treatment lessened EAE severity. IL15 knockout mice showed heightened susceptibility to EAE with significantly higher scores that were decreased by treatment with IL15. Thus, IL15 improves this CNS autoimmune disorder as a potential therapeutic agent.

Interleukin-15 expression is increased in human eosinophilic esophagitis and mediates pathogenesis in mice.

BACKGROUND & AIMS: Quantitative microarray analyses have shown increased expression of interleukin-15 (IL-15) messenger RNA in the esophagus of patients with eosinophilic esophagitis (EoE), a recently recognized allergic disorder with poorly understood pathogenesis. METHODS: Quantitative polymerase chain reaction and enzyme-linked immunosorbent assay analyses were performed to examine protein and transcript levels in tissue samples from patients with EoE. Tissues from IL-15Ra-deficient and wild-type (control) mice were also examined. Tissue eosinophilia was determined by immunostaining for major basic protein and flow cytometry for cell-surface receptors. RESULTS: Quantitative polymerase chain reaction analyses showed that levels of IL-15 and its receptor IL-15Ra were increased approximately 6- and approximately 10-fold, respectively, in tissues from patients with EoE and approximately 3- and approximately 4-fold, respectively, in mice with allergen-induced EoE. A >2-fold increase in serum IL-15 protein levels was also detected in human EoE samples compared with those from healthy individuals. Human IL-15 messenger RNA levels correlated with esophageal eosinophilia (P < .001). IL-15Ra-deficient mice were protected from allergen-induced esophageal eosinophilia compared with controls (P < .001), even though similar levels of airway eosinophilia were observed in all mice. IL-15 activated STAT5 and CD4(+) T cells to produce cytokines that act on eosinophils. Incubation of primary esophageal epithelial cells from mice and humans with IL-15 caused a dose-dependent increase in the mRNA expression and protein levels of eotaxin-1, -2, and -3. CONCLUSIONS: IL-15 mediates in the pathogenesis of EoE. IL-15 activates CD4(+) T cells to produce cytokines that act on eosinophils.

Interleukin-15 and its soluble receptor mediate the response to infliximab in patients with Crohn's disease.

BACKGROUND & AIMS: Infliximab is a monoclonal antibody against tumor necrosis factor that is used to treat patients with inflammatory bowel disease. We investigated serum levels and cellular expression of interleukin (IL)-15 and its receptor (sIL-15Ralpha) in patients with Crohn's disease (CD) treated with infliximab; and the effect on sIL-15Ralpha secretion by epithelial cells. METHODS: CD patients were given infliximab (n = 40; 3 infusions); 37 healthy controls were studied. Serum levels of IL-15, sIL-15Ralpha, and complex were determined by radioimmunoassay and cytokine levels by enzyme-linked immunosorbent assay. IL-15Ralpha and A Desintegrin and Metalloproteinase 17 levels were assessed by immunohistochemistry. Epithelial cell lines (HT-29 and Caco-2) were cultured with infliximab, adalimumab, or etanercept. Patients were classified as responders and nonresponders according to their Crohn's Disease Activity Index and clinical observations. RESULTS: Before infliximab, IL-15 was higher in responders than in controls and nonresponders. After infliximab, IL-15 decreased in responders while remaining stable in nonresponders. sIL-15Ralpha and IL-15/sIL-15Ralpha complex levels were higher in CD than in controls and increased only in responders after infliximab. IL-15Ralpha and A Desintegrin and Metalloproteinase 17 colocalized in epithelial cells and were higher in CD patients. In vitro, infliximab but not adalimumab and etanercept induced sIL-15Ralpha secretion by epithelial cells. CONCLUSIONS: Serum level of sIL-15Ralpha and the IL-15/sIL-15Ralpha complex increased in responder patients and the response was associated with a decrease of IL-15. Infliximab induced the release of the IL-15 receptor alpha, suggesting a specific modulation of IL-15 and its soluble receptor by reverse signaling through transmembrane tumor necrosis factor alpha.

Interleukin-15 and its receptor augment dendritic cell vaccination against the neu oncogene through the induction of antibodies partially independent of CD4 help.

Interleukin-15 (IL-15) stimulates the diffrentiation and proliferation of T, B, and natural killer cells; enhances CD8(+) cytolytic T-ceII activity; helps maintain CD44(hi)CD8(+) memory T cells; and stimulates immunoglobulin synthesis by B cells. IL-15 is trans-presented to effector cells by its receptor, IL-15Ralpha, expressed on dendritic cells (DC) and monocytes. We examined the antitumor effect of adenoviral-mediated gene transfer of IL-15 and IL-15Ralpha to augment a DC vaccine directed against the NEU (ErbB2) oncoprotein. Transgenic BALB-neuT mice vaccinated in late-stage tumor development with a DC vaccine expressing a truncated NEU antigen, IL-I5, and its receptor (DC(Ad.Neu+Ad_mIL-15+Ad.mlL-15Ralpha)) were protected from mammary carcinomas, with 70% of animals tumor-free at 30 weeks compared with none of the animals vaccinated with NEU alone (DC(Ad.Neu)). The combination of neu, IL-15, and IL-15Ralpha gene transfer leads to a significaintly greater anti-NEU antibody response compared with mice treated with DC(Ad.Neu) or DC(Ad.Neu) combined with either IL-15 (DC(Ad.Neu+Ad.mlL-15)) or lL-15Ralpha (DC(Ad.Neu+Ad.mlL-15Ralpha)). The antitumor effect was antibody mediated and involved modulation of NEU expression and signaIing. Depletion of CD4(+) cells did not abrogate the antitumor effect of the vaccine, nor did it inhibit the induction of anti-NEU aritibodies. Coexpression of IL-15 and IL-15Ralpha in an anticancer vaccine enhanced immune responses against the NEU antigen and may overcome impaired CD4(+) T-helper function.

High antitumor activity of RLI, an interleukin-15 (IL-15)-IL-15 receptor alpha fusion protein, in metastatic melanoma and colorectal cancer.

Interleukin (IL)-15 has an important role in tumor immunosurveillance and has a contemplated use in tumor immunotherapy. We have previously engineered the fusion protein RLI, composed of the NH(2)-terminal (amino acids 1-77, sushi+) domain of IL-15 receptor alpha coupled via a linker to IL-15, and shown that it displayed far better efficacy than IL-15 in vitro. In this report, we investigated in vivo whether RLI would be a better alternative than IL-15 and IL-2 for cancer treatment using two distinct animal models. B16F10 mouse melanoma cells were injected in C57BL/6 mice either i.v. or intrasplenically for lung or liver metastasis, respectively. HCT-116 human colorectal cancer cells were injected in the cecum of nude mice. We show that RLI has a higher efficiency than IL-15 or IL-2 to reduce lung and liver metastasis and enhance survival in the mouse B16F10 melanoma model, a result that was associated with a higher half-life in vivo. We also found that the antitumoral effect of RLI was completely abolished by in vivo depletion of natural killer cells using anti-asialoGM1 antibody. Moreover, RLI was also efficient to reduce by 50% tumor growth and the progression of metastasis of human colon carcinoma cells in an orthotopic nude mouse model. The fusion protein RLI has revealed strong anticancer effect in two different cancer models overcoming the limited effect of IL-15 by increasing its bioavailability and efficiency. These findings hold significant importance for the use of RLI as a potential adjuvant/therapeutic.

IL-7 and IL-15: biology and roles in T-Cell immunity in health and disease.

Cytokines IL-7 and IL-15 are essentially involved in T-cell homeostasis. IL-7 is required for developing mature T cells in the thymus, whereas in the periphery, it promotes the survival of naïve and memory T cells by upregulating the antiapoptotic molecule Bcl-2. IL-15 potently induces the proliferation of memory CD8+ T cells independently of antigen and augments their effector function. Although IL-7 and IL-15 may help to defend the host against microorganisms and tumors by promoting T-cell immunity, dysregulated production of IL-7 and IL-15 can be harmful. In fact, increased levels of IL-15 in the circulation and inflamed tissues have been reported in various autoimmune diseases, including rheumatoid arthritis (RA), possibly contributing to the pathogenesis. In addition, IL-7, which may induce the production of inflammatory cytokines from T cells and monocytes, are found to be elevated in the joints of patients with RA. Here, we review what is currently known about the roles of these cytokines in T-cell immunity, in general, as well as in RA, in particular, focusing on recent discoveries.

NKG2D signaling is coupled to the interleukin 15 receptor signaling pathway.

The effector functions of natural killer cells are regulated by activating receptors, which recognize stress-inducible ligands expressed on target cells and signal through association with signaling adaptors. Here we developed a mouse model in which a fusion of the signaling adaptor DAP10 and ubiquitin efficiently downregulated expression of the activating receptor NKG2D on the surfaces of natural killer cells. With this system, we identified coupling of the signaling pathways triggered by NKG2D and DAP10 to those initiated by the interleukin 15 receptor. We suggest that this coupling of activating receptors to other receptor systems could function more generally to regulate cell type-specific signaling events in distinct physiological contexts.

Rapid generation of a functional NK-cell compartment.

Bone marrow transplants are an important therapeutic tool for treating certain types of cancer as well as genetic diseases affecting the hematopoietic system. Until the transferred stem cells differentiate and reconstitute the immune system, recipients are at increased risk from opportunistic infections. We report the rapid generation of a functional natural killer (NK) compartment in lethally irradiated mice that received bone marrow cells from a syngeneic donor by treatment with IL-2/anti-IL-2 antibody complexes. We demonstrate that IL-2 complexes specifically expand the donor but not the host NK population and discuss the implications of this finding in the context of graft-versus-host disease and tumor relapse. Finally, we show that NK cells rapidly generated by IL-2 complexes kill MHC class I-deficient cells effectively in vivo. These data underline the unique therapeutic potential of IL-2 complexes.