Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The endometrium contains a distinct population of immune cells that undergo cyclic changes during the menstrual cycle and implantation. The majority of these leucocytes are uterine NK (uNK) cells, however how these cells interact with uterine stromal fibroblasts remains unclear. We therefore investigated the paracrine effect of medium conditioned by uterine decidual leucocytes (which are enriched for uNK cells) on the gene expression profile of endometrial stromal fibroblasts in vitro using a cDNA microarray. Our results, verified by real-time PCR, ELISA and FACS analysis, reveal that soluble factors from uterine leucocytes substantially alter endometrial stromal fibroblast gene expression. The largest group of up-regulated genes found was chemokines and cytokines. These include IL-8, CCL8 and CXCL1, which have also been shown to be stimulated by contact of stromal fibroblasts with trophoblast, suggesting that uNK cells work synergistically to support trophoblast migration during implantation. The decidual leucocytes also up-regulated IL-15 and IL-15Ralpha in stromal fibroblasts which could produce a niche for uNK cells allowing proliferation within and recruitment into the uterus, as seen in bone marrow. Overall this study demonstrates, for the first time, the paracrine communication between uterine leucocytes and uterine stromal fibroblasts, and adds to the understanding of how the uterine immune system contributes to the changes seen within the cycling endometrium.
Mol Hum Reprod 2009 Jan
PMID:Paracrine effects of uterine leucocytes on gene expression of human uterine stromal fibroblasts. 1908 35

The activating receptor NKG2D is mainly expressed by human CD8(+) T cells and NK cells but normally absent on CD4(+) T cells. However, a subset of autoreactive NKG2D(+)CD4(+) T cells has been found to exist in some autoimmune disease such as rheumatoid arthritis (RA) and to participate in the imbalance of immune response and inflammation. Up to date this observation has been extended to some autoimmune diseases such as RA and Crohn's disease and the mechanism underlying the presence of this type of NKG2D(+)CD4(+) T cells has not been delineated yet. In this study, we found that a substantial proportion of CD4(+) T cells expressed NKG2D in the PBMC of SLE patients. We also found that monocytes in SLE aberrantly expressed the NKG2D ligand of MHC class I chain-related (MIC) molecules and membrane-bound IL-15 (mIL-15) at the cell surface. When cultured with the sera from SLE patients, the monocytes from healthy volunteers could be induced to express MIC and mIL-15. However, this induced expression of MIC and mIL-15 could be blocked with anti-IFN-gamma receptor (anti-IFN-gammaR) antibody. We further demonstrated that NKG2D could be induced on normal CD4(+) T cells either cocultured with monocytes from patients with SLE, or monocytes from healthy volunteers but pretreated with IFN-gamma. Moreover, Th1 cytokines were found to be produced by NKG2D(+)CD4(+) T cells in the coculture system. By transwell assay, we found that both NKG2D expression and Th1 cytokines production depended on the cell-cell contact. These results indicate that the elevated sera IFN-gamma may be responsible for MIC and mIL-15 induction on monocytes in SLE; mIL-15 on monocytes contribute to NKG2D receptor induction on a subset of CD4(+) T cells. Moreover, CD14(+) monocytes promote NKG2D(+)CD4(+) T cells activation through the NKG2D-MIC engagement in the pathogenesis of SLE.
Mol Immunol 2009 Apr
PMID:Mutual activation of CD4+ T cells and monocytes mediated by NKG2D-MIC interaction requires IFN-gamma production in systemic lupus erythematosus. 1920 Jun 2

The recurrence of lesions and transmission of Herpes simplex virus is dependent on the number and function of viral specific CD8(+) T cells, especially the memory T cells. The generation, turnover and set point of this cell population is maintained by different factors like exposure to antigen, cytokines and co-stimulatory molecules. However, the contribution of these factors in the generation and maintenance of the memory CD8(+) T cell population is still controversial, since it is not clear if homeostatic proliferation driven by cytokines can overcome T cell receptor (TCR) signaling. Since, interleukin 15 (IL-15) and interleukin 21 (IL-21) are cytokines implicated in homeostatic control of CD8(+) T cell pool, we constructed and used expression plasmids coding for IL-15 (pIL-15) and IL-21 (pIL-21) to expand HSV specific CD8(+) T cells in an animal model. Our results showed that the IL-21 increased the frequency of CD8(+) T cells in the absence of antigen, although the magnitude of this response was dependent on TCR signaling. Both pIL-15 and pIL-21 boosted the numbers of antigen specific CD8(+) IFNgamma producing cells in the primary response. In the memory phase, numbers of CD8(+) CD44(high) as well as CD8(+) T cells producing IFN-gamma and TNF-alpha were increased when pIL-15 and pIL-21 were used alone or in combination, compared to vector treatment only, and association of antigen further increased the proliferative response. Our data suggest that genetic treatment with pIL-15 and pIL-21 in the presence or absence of cognate antigen can contribute to immune-enhancement against HSV.
Mol Immunol 2009 Apr
PMID:IL-21 and IL-15 cytokine DNA augments HSV specific effector and memory CD8+ T cell response. 1923 74

Human interleukin 15 (hIL15) is a soluble cytokine that plays a key role in the maintenance of long-lasting responses against pathogens and a valuable target for the treatment of autoimmune diseases. In this study, we sought to elucidate the thermodynamic basis of the recognition mechanism for its private alpha-receptor (hIL15Ralpha), considered the first step of the interleukin's activation pathway. Binding of wild-type hIL15 to its alpha-receptor is characterized by a very slow dissociation rate constant and driven by a favorable enthalpy change. We further studied the kinetic and energetic consequences of substituting residues of hIL15 located at the contact interface by means of the surface plasmon resonance technique. Replacement of negatively charged residues with Ala indicates that the energetics of interaction is primarily driven by electrostatic forces, manifested by a dramatic acceleration of the dissociation step and a reduction of favorable binding enthalpy. Our analyses also unveiled a novel and critical role for residue Tyr26 in the interaction, which facilitates desolvation of key charged residues during the assembly of the complex. These results were rationalized in terms of a previously reported structure of hIL15.hIL15alpha, demonstrating that the binding energetics is dominated by interactions occurring at three hot spots whose spatial locations coincide with a previously proposed structural division of the contact interface in three regions. Specifically, Region 1 is the main contributor to the binding energy of the complex by establishing very favorable electrostatic interactions with the receptor; Region 2 is also dominated by electrostatic forces, although of a lesser intensity; and Region 3 confers specificity to the association by means of high shape complementarity and by bringing additional stabilization energy to the complex. The biological impact of hIL15 mutations with the most effect on alpha-receptor binding was evaluated in a cell-based proliferation assay, validating the conclusions of our thermodynamic analyses and highlighting the functional importance of molecular contacts that promote prolonged binding of the interleukin to the alpha-receptor. In closing, the thermodynamics and physicochemical nature of the interactions observed in IL15h.IL15Ralpha complex, together with interactions in Region 3 of the interleukin, poses a stark contrast with the structurally related and sometimes functionally redundant interleukin 2.
J Mol Biol 2009 Jun 26
PMID:Contributions of interfacial residues of human Interleukin15 to the specificity and affinity for its private alpha-receptor. 1940 27

Anabolic hormones, including testosterone, have been suggested as a therapy for aging-related conditions, such as osteoporosis and sarcopenia. These therapies are sometimes associated with severe androgenic side effects. A promising alternative to testosterone replacement therapy are selective androgen receptor modulators (SARMs). SARMs have the potential to mimic the desirable central and peripheral androgenic anabolic effects of testosterone without having its side effects. In this study we evaluated the effects of LGD2941, in comparison to testosterone, on mRNA expression of selected target genes in whole blood in an non-human model. The regulated genes can act as potential blood biomarker candidates in future studies with AR ligands. Cynomolgus monkeys (Macaca fascicularis) were treated either with testosterone or LGD2941 for 90 days in order to compare their effects on mRNA expression in blood. Blood samples were taken before SARM application, on day 16 and on day 90 of treatment. Gene expression of 37 candidate genes was measured using quantitative real-time RT-PCR (qRT-PCR) technology. Our study shows that both testosterone and LGD2941 influence mRNA expression of 6 selected genes out of 37 in whole blood. The apoptosis regulators CD30L, Fas, TNFR1 and TNFR2 and the interleukins IL-12B and IL-15 showed significant changes in gene expression between control and the treatment groups and represent potential biomarkers for androgen receptor ligands in whole blood.
J Steroid Biochem Mol Biol 2009 Apr
PMID:Influence of testosterone and a novel SARM on gene expression in whole blood of Macaca fascicularis. 1942 47

Both NK cells and IL-15 play crucial roles in innate immunity against viral infections and cancer. Cigarette smoke is known to increase susceptibility to infections and certain cancers. Interleukin (IL)-15 plays an important role in immune responses by regulating proliferation, survival and functions of NK cells. Here, we examined the impact of cigarette smoke on IL-15 production and IL-15 mediated NK cell functions in human PBMCs. We report that cigarette smoke significantly suppresses the induction of IL-15 by poly I:C in human PBMCs. Serum IL-15 levels among smokers was significantly lower than non-smokers. In contrast to a profound increases in intracellular IL-15/IL-15Ralpha in poly I:C-treated PBMCs, exposure of PBMCs to smoke-conditioned media (SCM) diminished the IL-15/IL-15Ralpha production. We examined if inhibition of IL-15 production could lead to less NK cell activation. Interestingly, SCM-treated PBMCs had diminished up-regulation of NK cell activation marker, CD69, but not NKG2D compared with controls after poly I:C stimulation. We then confirmed by using IL-15 neutralizing antibody as well as exogenous IL-15 that the ploy I:C-induced NK cells activation was IL-15 mediated. More importantly, cigarette smoke significantly impaired NK cell cytolytic potential to kill K562 cancer cells which was found to be IL-15 mediated. The inhibition of IL-15 and its regulatory NK cell activities were linked to attenuated STAT3 and STAT5, but not ERK1/2 phosphorylations. We demonstrate, for the first time, that cigarette smoke compromises IL-15 production and as a result NK cell function which could link to the higher incidence of cancers or viral infections observed among smokers.
Mol Immunol 2009 Sep
PMID:Exposure to cigarette smoke suppresses IL-15 generation and its regulatory NK cell functions in poly I:C-augmented human PBMCs. 1959 95

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.
Mol Cancer Ther 2009 Sep
PMID:High antitumor activity of RLI, an interleukin-15 (IL-15)-IL-15 receptor alpha fusion protein, in metastatic melanoma and colorectal cancer. 1972 83

Different studies have revealed that the Ca2+-dependent serine/threonine phosphatase calcineurin is involved in the regulation of adipocyte differentiation. Calcineurin acts as a Ca2+-dependent molecular switch that negatively regulates the ability of 3T3-L1 cells to undergo adipocyte differentiation by preventing the expression of critical proadipogenic transcription factors. In this study we investigated the role of interleukin-15 (IL-15), a cytokine previously known to be involved in the control of fat accretion by adipose cells, in the differentiation of the 3T3-L1 preadipose cell line. We found that IL-15 is able to increase alpha-calcineurin mRNA content in white adipose tissue of rats chronically treated with the cytokine and also in the 3T3-L1 preadipose cell line. Moreover, IL-15 promoted a decrease in both leptin mRNA expression and lipid accumulation, as estimated by Red Oil O staining. Cotreatment with IL-15 and FK506 (a calcineurin inhibitor) resulted in no changes in lipid content compared with the non-treated group. These data suggest that IL-15 directly inhibits adipogenesis, possibly by upregulating alpha-calcineurin and preventing the induction of adipocyte differentiation.
Int J Mol Med 2009 Oct
PMID:Interleukin-15 increases calcineurin expression in 3T3-L1 cells: possible involvement on in vivo adipocyte differentiation. 1972 84

Red blood cells (RBC) have emerged as a novel regulatory cell type endowed with bioactivities toward activated human T cells. Herein we show that the RBC bioactivities act on intracellular pathways initiated by T cell receptor (TCR)-dependent and -independent stimuli,including IL-2, IL-15, and the mixture of phorbol dibutyrate and ionomycin. The RBC bioactivities preserve the antioxidant status and are capable of rescuing activated T cells from cell death induced by serum deprivation. They are not mediated by glycosylphosphatidylinositol-linked receptors or sialic acids, and kinetic studies revealed that they hasten the entrance into the cell cycle. By using cyclosporine A (CsA) and rapamycin (Rapa) we show that the RBC bioactivities are calcineurin-dependent. Thus, treatment of T cells with CsA, but not Rapa, impaired RBC bioactivities, and preincubation of RBC with CsA completely abolished their bioactivities. We have demonstrated that RBC carry out bioactivities that are sensitive to CsA.
Cell Mol Life Sci 2009 Oct
PMID:Red blood cells carry out T cell growth and survival bioactivities that are sensitive to cyclosporine A. 1972 58

Being exposed to food products, pathogens and harmless commensal bacteria, the mucosal immune system faces a constant challenge. Therefore, maintenance of a homeostatic balance is required to achieve tolerance to harmless bacteria and their products and to induce potent immunity to infection with pathogenic bacteria. Until recently, the literature on mucosal natural killer (NK) cells residing in the intestinal lamina propria was scarce and phenotype and function of gut mucosal NK cells did not receive much attention. Recently, data have become available identifying two distinct subsets of mucosal NKp46(+) lymphocytes based on the expression of the orphan transcription factor RORgammat. In many ways, the RORgammat(-) subset resembled "classical" NK cells in that it was developmentally dependent on IL-15 but not on RORgammat and displayed NK cell function (e.g., cell-mediated cytotoxicity, IFN-gamma production). In contrast, the RORgammat(+) subset developed independent of IL-15 but required RORgammat, suggesting that this subset may be related to lymphoid tissue inducer (LTi) cells. Interestingly, these RORgammat(+) NKp46(+) NK-LTi cells constitutively produced large amounts of IL-22, a cytokine regulating antimicrobial protection and regeneration of epithelial cells. In this chapter, we provide experimental procedures to isolate "classical" NK cells from the intestinal lamina propria as well as the newly described lymphoid tissue inducer-like (LTi-like) cells producing IL-22 and co-expressing NK cell receptors.
Methods Mol Biol 2010
PMID:Isolation of NK cells and NK-like cells from the intestinal lamina propria. 2003 61


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