Disease relevance of GNLY

• In vivo effects of GNLY were evaluated using the syngeneic T lymphoma tumor C6VL [1].
• Granulysin (GNLY) is a cytolytic molecule expressed by human CTL and NK cells with activity against a variety of tumors and microbes, including Mycobacterium tuberculosis [1].
• We propose that CD8(+)CD57(+) cells were Ag-driven effector cells with very high cytotoxic effector potential including perforin, granzymes, and granulysin, regardless of HIV status [2].
• Uptake of granulysin via lipid rafts leads to lysis of intracellular Listeria innocua [3].
• Pertussis toxin treatment abrogates chemoattraction by granulysin, indicating involvement of G-protein-coupled receptor(s) [4].

Psychiatry related information on GNLY

• We developed a novel vaccine formulation by incorporating Id protein with liposomal lymphokine that was more potent than a prototype, carrier-conjugated Id protein vaccine in preclinical studies [5].
• We have previously shown that this marker is profusely expressed in cortex of elderly and Alzheimer's disease (AD) patients, as is the receptor for the lymphokine interleukin-2 [6].
• Lifestyles and mental health status are associated with natural killer cell and lymphokine-activated killer cell activities [7].

High impact information on GNLY

• The intricate causal relationships among ion channels, membrane potential, [Ca2+]i, and lymphokine gene expression can now be pursued at the single-cell level with patch-clamp recording, calcium-dependent dyes, reporter genes, and fluorescence video techniques [8].
• Lymphokine production by human T cells in disease states [9].
• Altered profiles of lymphokine production may account for immune dysfunctions in some primary or acquired immunodeficiency syndromes [9].
• The identification of downstream effectors, including calcineurin and Ras, that regulate cellular responses, such as lymphokine gene expression, promises the future possibility of connecting the complex pathway from the plasma membrane to the nucleus in lymphocytes [10].
• The lymphokine gamma-interferon, a strong inducer of Class II genes in a variety of normal cells, did not restore Class II gene expression in any of the SCID B-cell lines [11].

Chemical compound and disease context of GNLY

• Combined effect of epirubicin and lymphokine-activated killer cells on the resistant human breast cancer cells [12].
• We have used this monoclonal antibody to study the course of Fc gamma Rlo appearance on bone marrow cells, leukocytes of patients with chronic myelogenous leukemia (CML), and HL-60 and U937 cells induced to differentiate with agents such as dimethyl sulfoxide (DMSO), retinoic acid, phorbol myristate acetate, and lymphokine [13].
• The lymphokine enhanced the antimicrobial activity of dexamethasone-treated macrophages against Listeria and Salmonella but not against Aspergillus or Nocardia [14].
• Fibronectin and alpha5 integrin regulate keratinocyte cell cycling. A mechanism for increased fibronectin potentiation of T cell lymphokine-driven keratinocyte hyperproliferation in psoriasis [15].
• The anti-human serum albumin (HSA) B-cell repertoire of C57BL/6 mice was examined by culturing splenocytes at limiting dilution following polyclonal stimulation with Escherichia coli lipopolysaccharide and a lymphokine mixture [16].

Biological context of GNLY

• IL-15-activated CD8 T cells acquired anticryptococcal activity, which correlated with the up-regulation of granulysin [17].
• Although the molecular mechanism of GNLY-induced apoptosis of Jurkat T cells is well defined in vitro, no direct evidence for its in vivo effects has been demonstrated [1].
• GNLY is expressed in leukocytes from transgenic mice with similar kinetics as in PBMC from humans: GNLY is constitutively expressed in NK cells and, following stimulation through the TCR, appears in T lymphocytes 8-10 days after activation [1].
• Because there is no murine homologue of GNLY, we generated mice expressing GNLY using a bacterial artificial chromosome containing the human GNLY gene and its 5' and 3' flanking regions [1].
• Neither the DNA sequence determined from a full-length cDNA clone overlapping with clone AH2-519 nor the amino acid sequence of its predicted protein product has significant homology to published sequences in the GenBank or NBRF databases [18].

Anatomical context of GNLY

• Following stimulation by the C. neoformans mitogen, CD8 T cells expressed granulysin and acquired antifungal activity [17].
• Allospecific cell lines generated from GNLY transgenic animals showed enhanced killing of target cells [1].
• GNLY mRNA is highest in spleen, with detectable expression in thymus and lungs, and minimal expression in heart, kidney, liver, muscle, intestine, and brain [1].
• Human tumor cell line resistance to chemotherapeutic agents does not predict resistance to natural killer or lymphokine-activated killer cell-mediated cytolysis [19].
• Lymphocyte activation was determined by measurement of proliferative responses and lymphokine release [20].

Associations of GNLY with chemical compounds

• Concanamycin A and EGTA did not affect the antifungal effect, suggesting that the activity of granulysin was perforin independent [17].
• Unlike 519, the predicted NKG5 polypeptide has an NH2-terminal sequence that is strongly hydrophobic, characteristic of a signal peptide, and lacks any additional hydrophobic regions in the remainder of the peptide, suggesting that NKG5 encodes a secreted protein [21].
• In contrast to previous findings in mice, the arginine analogue, NG-monomethyl-L-arginine, significantly inhibited both proliferation and lymphokine release by superantigen-stimulated human cells [20].
• Thus, our results demonstrate that pyocyanine inhibits T cell proliferation by decreasing the production of the critical lymphokine IL 2 and by decreasing the expression of the IL 2 receptor [22].
• RESULTS: Granulysin mRNA increase (vs. 95% confidence interval of 159 urine samples from nonrejecting patients) was detected during 11 of 14 aRx episodes, and follow-up studies showed its predictive value for delayed aRx episodes, even weeks before enhanced serum creatinine was observed [23].

Physical interactions of GNLY

• Opposing roles of activator protein-1 and CCAAT/enhancer binding protein beta in the regulation of inducible granulysin gene expression in a human monocytic cell line, THP-1 [24].

Regulatory relationships of GNLY

• The resultant IL-15 activates CD8 T cells to express granulysin, which is responsible for antifungal activity [17].
• Lymphokine-activated killer cell susceptibility and multidrug resistance in small cell lung carcinoma [25].
• Granulysin induction was associated with enhanced regulated on activation normal T-cell expressed and secreted (RANTES) mRNA expression in 8 of 11 samples [23].
• The lymphokine upregulated 35S-labeled PAI-1 protein expression in orbital fibroblasts in dose-dependent manner [26].
• Nevertheless, activation of caspase 3 is observed in granulysin-treated cells, suggesting that granulysin activates a novel pathway of CTL- and NK cell-mediated death distinct from granzyme- and death receptor-induced apoptosis [27].

Other interactions of GNLY

• In addition to classic MDR, RV+ cells displayed relative resistance to complement-mediated cytotoxicity with both immunoglobulin G and M antibodies against different cell surface antigens, but not to antibody-dependent cellular cytotoxicity and lymphokine-activated killing [28].
• Furthermore, IL-15 was both necessary and sufficient for granulysin up-regulation in CD8 T cells [17].
• CONCLUSIONS: We demonstrate the upregulation of immune-related genes IL-15Ralpha, Lpn and NKG5 in secretory versus proliferative human endometrium [29].
• These experiments demonstrate the production of a human lymphocyte factor (lymphokine) that induces LP synthesis [30].
• The 9-kDa product is a processed form of 519 and differs from the 15-kDa product in both its amino and carboxyl terminus [31].

Analytical, diagnostic and therapeutic context of GNLY

• Southern blot and DNA sequence analyses suggest that NKG5 and 519 mRNAs are transcripts from a single gene that has allelic polymorphism [21].
• In the present study, we report soluble TR6-Fc or solid-phase TR6-Fc costimulated proliferation, lymphokine production, and cytotoxicity of human T cells in the presence of TCR ligation [32].
• Recombinant granulysin was found to be actively taken up by DC into early endosomal Ag 1-labeled endosomes, as detected by immunofluorescence [3].
• Enhanced granulysin mRNA expression in urinary sediment in early and delayed acute renal allograft rejection [23].
• Sequence analysis of the granulysin and granzyme B genes in familial hemophagocytic lymphohistiocytosis [33].

References