Disease relevance of IL32

• In conclusion, NK4 gene therapy is a promising strategy to treat HCC based on the pleiotropic functions of NK4 interfering with tumor growth, invasion, metastasis and angiogenesis [1].
• METHODS: Cells from the LS174T human colonic adenocarcinoma cell line were infected with recombinant adenovirus rvAdCMV/NK4 and the effects of the manipulation on tumor cell proliferation, scatter, migration, and basement membrane invasion were assessed [2].
• CONCLUSION: NK4 inhibits glioblastoma growth in vivo, most likely via antimitogenic, antimotogenic, proapoptotic, and antiangiogenic mechanisms [3].
• Functional effects of NK4 on glioma and endothelial cells were analyzed in vitro [3].
• We have examined here the properties of NK4, an HGF variant containing the N-terminal hairpin plus the 4 kringle domains, on tumour cell proliferation, dissociation and invasion using human colorectal cancer cells (HT115) [4].
• In the inflamed synovial tissues from rheumatoid arthritis patients, interleukin-32 is prominently expressed and correlates with the severity of arthritis and the expression of other cytokines, including TNF-alpha and interleukin-1 [5].
• A strong expression of IL-32alpha was detected in the pancreatic cancer cells [6].

Psychiatry related information on IL32

• Sixty-nine schizophrenic patients (52 men and 17 women) who were consecutive admissions to Shehar Psychiatric Hospital, Taif, Saudi Arabia, were investigated for the phenomenology and frequency of visual hallucinations [7].
• Five hundred and fifty one epileptic cases in Taif Mental Health Hospital in Saudi Arabia were studied [8].

High impact information on IL32

• Human IL-32 exists as four splice variants, and IL-32 from other species were found as expressed sequence tag clones in the databank [9].
• The affinity of IL-32alpha to PR3 was determined by surface plasmon resonance [10].
• Here, we used ligand (IL-32alpha) affinity chromatography in an attempt to isolate an IL-32alpha soluble receptor or binding protein [10].
• Immunohistochemistry revealed that IL-32 is highly expressed in RA synovial tissue biopsies, whereas IL-32 was not observed in synovial tissues from patients with osteoarthritis [11].
• IL-32 was a potent inducer of prostaglandin E(2) release in mouse macrophages and human blood monocytes, an important property for inflammation [11].

Chemical compound and disease context of IL32

• NK4-expression suppressed the gefitinib-resistance induced by the interaction between fibroblasts and SGC, and eventually, this tailor-made combination synergistically decelerated the disease progression by inhibiting proliferative, angiogenic and antiapoptotic effects in tumor tissues [12].
• In addition, the inhibitory effect of cisplatin (CDDP) on peritoneal metastasis was significantly enhanced by AxCANK4, suggesting that the combination of intraperitoneal (i.p.) chemotherapy with NK4 gene therapy might be effective, even in cases of advanced peritoneal metastasis from gastric cancer [13].
• The aim of this study was to evaluate the therapeutic efficacy of Ad-NK4 in combination with gemcitabine (GEM) against pancreatic cancer [14].

Biological context of IL32

• Moreover, transduced HCC cells produced sufficient amounts of NK4 protein to achieve bystander effects involving reduced migration of nontransduced tumor cells and reduced proliferation of endothelial cells [1].
• AIM: To investigate the inhibitory effects of a recombinant adenovirus vector that expresses NK4, a truncated form of human hepatocyte growth factor (HGF), on human colonic adenocarcinoma cells in vitro to establish a basis for future NK4 gene cancer therapy [2].
• Proteinase 3 is an IL-32 binding protein [10].
• Portions of an alpha chain containing an N-terminal segment and four kringle domains (NK4) antagonize HGF activity [15].
• We have isolated a cDNA clone from a human activated NK cell-derived cDNA library that identifies a transcript (NK4) that is selectively expressed in lymphocytes [16].

Anatomical context of IL32

• Therefore, we evaluated the effects of adenoviral vector-mediated expression of NK4 on the biological behavior of a series of HCC cell lines in vitro and on HepG2 xenografts in vivo [1].
• NK4 is an hepatocyte growth factor (HGF)-antagonist and a broad angiogenesis inhibitor [1].
• RESULTS: We found that rvAdCMV/NK4 expression attenuated HGF-induced tumor cell scatter, migration, and basement membrane invasion (P<0.05), but did not inhibit tumor cell proliferation [2].
• Moreover, after limited cleavage by PR3, IL-32alpha was more active than intact IL-32alpha in inducing macrophage inflammatory protein-2 in mouse macrophages and IL-8 in human peripheral blood mononuclear cells [10].
• Here we show that chymases, which are chymotryptic peptidases secreted by mast cells, hydrolyze HGF, thereby abolishing scatter factor activity while generating an NK4-like antagonist of HGF scatter factor activity [15].

Associations of IL32 with chemical compounds

• Animal models were orally administrated gefitinib (50 mg/kg/day, on days 7-28), and peritoneally NK4-expressing ternary complex (on days 14, 21 and 28) [12].
• Controlled release by a biodegradable hydrogel enabled the NK4 plasmid DNA to exert the tumor suppression effects [17].
• Dextran was cationized by introducing spermine to the hydroxyl groups to allow for polyionic complexation with NK4 plasmid DNA [18].
• Likewise, intrahepatic invasion of cancer cells was inhibited by NK4 gene expression, and this anti-invasive effect was associated with in situ inhibition of c-Met receptor tyrosine phosphorylation [19].
• When specific caspase inhibitors were used, the synergism between IL-32 and MDP/NOD2 depended on the activation of caspase 1 [20].
• RA FLS expressed and secreted IL-32 when stimulated with tumor necrosis factor alpha (TNFalpha) [21].

Physical interactions of IL32

• HGF/NK4 competitively inhibited the specific binding of HGF to the receptor [22].

Regulatory relationships of IL32

• HGF/NK4 inhibited VEGF-induced angiogenesis in in vitro cultured endothelial cells and in vivo rabbit model [23].
• In addition, HGF/SF-stimulated invasion of endothelium by breast cancer cells was inhibited by the addition of NK4 [24].

Other interactions of IL32

• Inhibition of angiogenesis and HGF-cMET-elicited malignant processes in human hepatocellular carcinoma cells using adenoviral vector-mediated NK4 gene therapy [1].
• However, limited cleavage of IL-32alpha by PR3 enhances activities of the cytokine [10].
• Nevertheless, HGF/NK4 did not affect phosphorylation of VEGF receptor-2 [kinase domain region (KDR)/foetal liver kinase (Flk)-1] [23].
• NK4 had no effects on interleukin 8- and vascular endothelial growth factor-induced tubule formation [25].
• Cell proliferation in vivo, evaluated by immunohistochemical staining of proliferating cell nuclear antigen, did not differ between NK4 and mock transfectants, and this was also the finding in the in vitro assay [26].

Analytical, diagnostic and therapeutic context of IL32

• NK4 gene therapy has confirmed antitumor efficacy on cancers with intact HGF-cMET signaling pathway [1].
• Southern blot analysis of B lymphoblastoid lines derived from 18 unrelated individuals reveal variable banding patterns suggestive of polymorphism within the NK4 gene [16].
• Our present findings further support the potential use of NK4 during radiotherapy for patients with pancreatic cancer [27].
• The enhanced invasiveness of pancreatic cancer cells induced by coculture with irradiated fibroblasts was completely blocked by NK4, a specific antagonist of HGF [27].
• Furthermore, systemic NK4 delivery by intraperitoneal injection of AdCMV.NK4 effectively suppressed both angiogenesis in the Matrigel assay (86% reduction, P<0.032), subcutaneous tumor growth in vivo (by 65% for H358, P<0.001), and hematogenous lung metastases without obvious side effects [28].

References