A novel role for interleukin 32 in cholestasis.
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ABSTRACT:
SUBMITTER: Zhang X
PROVIDER: S-EPMC8611182 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Interleukin-32 (IL-32) was originally identified in natural killer (NK) cells activated by IL-2 in 1992. Thus, it was named NK cell transcript 4 (NK4) because of its unknown function at that time. The function of IL-32 has been elucidated over the last decade. IL-32 is primarily considered to be a booster of inflammatory reactions because it is induced by proinflammatory cytokines and stimulates the production of those cytokines and vice versa. Therefore, many studies have been devoted to studying the roles of IL-32 in inflammationassociated cancers, including gastric, colon cancer, and hepatocellular carcinoma. At the same time, roles of IL-32 have also been discovered in other cancers. Collectively, IL-32 fosters the tumor progression by nuclear factor-?B (NF-?B)-mediated cytokines and metalloproteinase production, as well as stimulation of differentiation into immunosuppressive cell types in some cancer types. However, it is also able to induce tumor cell apoptosis and enhance NK and cytotoxic T cell sensitivity in other cancer types. In this review, we will address the function of each IL-32 isoform in different cancer types studied to date, and suggest further strategies to comprehensively elucidate the roles of IL-32 in a contextdependent manner. [BMB Reports 2019; 52(3): 165-174].
| S-EPMC6476484 | biostudies-literature
Project description:OBJECTIVE:Efforts to manage non-alcoholic fatty liver disease (NAFLD) are limited by the incomplete understanding of the pathogenic mechanisms and the absence of accurate non-invasive biomarkers. The aim of this study was to identify novel NAFLD therapeutic targets andbiomarkers by conducting liver transcriptomic analysis in patients stratified by the presence of the PNPLA3 I148M genetic risk variant. DESIGN:We sequenced the hepatic transcriptome of 125 obese individuals. 'Severe NAFLD' was defined as the presence of steatohepatitis, NAFLD activity score ?4 or fibrosis stage ?2. The circulating levels of the most upregulated transcript, interleukin-32 (IL32), were measured by ELISA. RESULTS:Carriage of the PNPLA3 I148M variant correlated with the two major components of hepatic transcriptome variability and broadly influenced gene expression. In patients with severe NAFLD, there was an upregulation of inflammatory and lipid metabolism pathways. IL32 was the most robustly upregulated gene in the severe NAFLD group (adjusted p=1×10-6), and its expression correlated with steatosis severity, both in I148M variant carriers and non-carriers. In 77 severely obese, and in a replication cohort of 160 individuals evaluated at the hepatology service, circulating IL32 levels were associated with both NAFLD and severe NAFLD independently of aminotransferases (p<0.01 for both). A linear combination of IL32-ALT-AST showed a better performance than ALT-AST alone in NAFLD diagnosis (area under the curve=0.92 vs 0.81, p=5×10-5). CONCLUSION:Hepatic IL32 is overexpressed in NAFLD, correlates with hepatic fat and liver damage, and is detectable in the circulation, where it is independently associated with the presence and severity of NAFLD.
| S-EPMC7497582 | biostudies-literature
Project description:BackgroundVarious proinflammatory cytokines can be detected within the melanoma tumor microenvironment. Interleukin 32 (IL32) is produced by T cells, NK cells and monocytes/macrophages, but also by a subset of melanoma cells. We sought to better understand the biology of IL32 in human melanoma.MethodsWe analyzed RNA sequencing data from 53 in-house established human melanoma cell lines and 479 melanoma tumors from The Cancer Genome Atlas dataset. We evaluated global gene expression patterns associated with IL32 expression. We also evaluated the impact of proinflammatory molecules TNFα and IFNγ on IL32 expression and dedifferentiation in melanoma cell lines in vitro. In order to study the transcriptional regulation of IL32 in these cell lines, we cloned up to 10.5 kb of the 5' upstream region of the human IL32 gene into a luciferase reporter vector.ResultsA significant proportion of established human melanoma cell lines express IL32, with its expression being highly correlated with a dedifferentiation genetic signature (high AXL/low MITF). Non IL32-expressing differentiated melanoma cell lines exposed to TNFα or IFNγ can be induced to express the three predominant isoforms (α, β, γ) of IL32. Cis-acting elements within this 5' upstream region of the human IL32 gene appear to govern both induced and constitutive gene expression. In the tumor microenvironment, IL32 expression is highly correlated with genes related to T cell infiltration, and also positively correlates with high AXL/low MITF dedifferentiated gene signature.ConclusionsExpression of IL32 in human melanoma can be induced by TNFα or IFNγ and correlates with a treatment-resistant dedifferentiated genetic signature. Constitutive and induced expression are regulated, in part, by cis-acting sequences within the 5' upstream region.
| S-EPMC6449995 | biostudies-literature
Project description:http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-3-reading-santiago a video presentation of this article http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-3-interview-levy an interview with the author https://www.wileyhealthlearning.com/Activity/7058605/disclaimerspopup.aspx quertions and earn CME.
| S-EPMC7128034 | biostudies-literature
Project description:Visceral leishmaniasis (VL) is a chronic parasitic disease caused by Leishmania infantum in the Americas. During VL, several proinflammatory cytokines are produced in spleen, liver, and bone marrow. However, the role of interleukin-32 (IL-32) has not been explored in this disease. IL-32 can induce production of proinflammatory cytokines in innate immune cells and polarize the adaptive immune response. Herein, we discovered that L. infantum antigens induced expression of mRNA mainly for the IL-32? isoform but also induced low levels of the IL-32? transcript in human peripheral blood mononuclear cells. Furthermore, infection of human IL-32? transgenic mice (IL-32?Tg mice) with L. infantum promastigote forms increased IL-32? expression in the spleen and liver. Interestingly, IL-32?Tg mice harbored less parasitism in the spleen and liver than wild-type (WT) mice. In addition, IL-32?Tg mice showed increased granuloma formation in the liver compared to WT mice. The protection against VL was associated with increased production of nitric oxide (NO), interferon gamma (IFN-?), IL-17A, and tumor necrosis factor alpha by splenic cells restimulated ex vivo with L. infantum antigens. In parallel, there was an increase in the number of Th1 and Th17 T cells in the spleens of IL-32?Tg mice infected with L. infantum IL-32? induction of IFN-? and IL-17A expression was found to be essential for NO production by splenic cells of infected animals. These data indicate that IL-32? potentiates the Th1/Th17 immune response during experimental VL, thus contributing to the control of L. infantum infection.
| S-EPMC5913854 | biostudies-other
Project description:Interleukin-32 (IL-32) is a pro-inflammatory cytokine and its effects in various inflammatory diseases have been investigated. However, the role of IL-32 on atherosclerosis, an inflammatory disease, remains unknown. The present study examined the use of IL-32?, the most abundant transcript of IL-32, in the treatment of oxidized low-density lipoprotein (ox-LDL)-stimulated THP-1 macrophages for 24 h, which simulates a foam cell formation model. The effect of IL-32? (20, 50 and 100 ng/ml) on lipid deposition in the macrophages was analyzed using Oil Red O staining, while the cholesterol efflux on apolipoprotein A-I was also measured. The mRNA and protein expression levels of peroxisome proliferator-activated receptor ? (PPAR?), liver X receptor ? (LXR?), ATP-binding cassette transporter A1 (ABCA1) and ABCG1 were quantified by reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. The results indicated that IL-32? exposure enhanced the lipid deposition and attenuated the cholesterol efflux from ox-LDL-stimulated THP-1 macrophages in a dose-dependent manner. Furthermore, the expression levels of ABCA1, LXR? and PPAR? were dose-dependently decreased by IL-32? at the mRNA and protein levels. Addition of the PPAR? agonist 15d-PGJ2 or overexpression of PPAR? in THP-1 macrophages abrogated the IL-32?-mediated inhibition of cholesterol efflux and reversed the IL-32?-mediated downregulation of ABCA1 and LXR?. In conclusion, IL-32? enhances lipid accumulation and inhibits cholesterol efflux from ox-LDL-exposed THP-1 macrophages by regulating the PPAR?-LXR?-ABCA1 pathway.
| S-EPMC5526182 | biostudies-literature
Project description:BackgroundHerpes simplex virus type 2 (HSV-2; herpes) exacerbates human immunodeficiency virus type 1 (HIV) by unclear mechanisms. These studies tested the impact of HSV-2 on systemic T-cells and HIV reservoirs.MethodsPeripheral blood mononuclear cells from HIV-infected women on antiretroviral therapy who were HSV-2 seropositive or seronegative and HIV-uninfected controls were analyzed by flow cytometry. Cell-associated HIV DNA and RNA were quantified in the absence or presence of activating stimuli, recombinant interleukin 32γ (IL-32γ), and a RUNX1 inhibitor. RNA was assessed by nanostring.ResultsCD4, but not CD8, T-cell phenotypes differed in HIV+/HSV-2+ versus HIV+/HSV-2- (overall P = .002) with increased frequency of CCR5+, CXCR4+, PD-1+, and CD69+ and decreased frequency of CCR10+ and CCR6+ T-cells. The changes were associated with higher HIV DNA. Paradoxically, IL-32, a proinflammatory cytokine, was lower in subpopulations of CD4+ T-cells in HSV-2+ versus HSV-2- women. Recombinant IL-32γ blocked HIV reactivation in CD4+ T-cells and was associated with an increase in RUNX1 expression; the blockade was overcome by a RUNX1 inhibitor.ConclusionsHerpes is associated with phenotypic changes in CD4+ T-cells, including a decrease in IL-32, which may contribute to increased HIV reservoirs. Blocking IL-32 may facilitate HIV reactivation to improve shock and kill strategies.
| S-EPMC5388286 | biostudies-literature
Project description:Intrahepatic cholestasis of pregnancy (ICP) is an idiopathic liver disease while the biochemical characteristic is the elevated level of total bile acid (TBA). The present study investigated whether miR-148a mediates the induced effect of estrogen on the development of ICP and the proper mechanism: PXR/MRP3 signal pathway. mRNA expression was detected by qPCR, protein expression was detected by western blotting, the concentration of estrogen and TBA were detected by reagent kit respectively. In the cinical research, it was found that miR-148a expression was positive related with the concentration of TBA in the serum of ICP patients. In in vitro research, estradiol (500 nmol/L, 12 h) significantly upregulated miR-148a expression and LV-148a-siRNA inhibited the function of estradiol (500 nmol/L, 48 h) on TBA secretion. In addition, gene silence of miR-148a upregulated PXR expression which was inhibited by estradiol in LO2 cells. Pretreatment of rifampin (10 ?mol/L), the agonist of PXR alleviated the TBA secretion induced by estradiol (500 nmol/L, 48 h). miR-148a-siRNA and PXR had a synergistic action on TBA secretion of LO2. Both of miR-148a-siRNA and rifampin (10 ?mol/L) inhibited the upregulated effect of estradiol on MRP3 expression. This research has demonstrated that miR-148a may be involved in the induction of estrogen on ICP via PXR signal pathway, and MRP3 may be involved.
| S-EPMC5457162 | biostudies-literature
Project description:BackgroundInterleukin-32 (IL-32) is a recently discovered proinflammatory cytokine involved in inflammatory diseases. We investigated the expression of IL-32 and its regulation mechanism in the inflammatory response of patients with Helicobacter pylori (H. pylori) infection.Design and methodsIL-32 mRNA and protein expression in gastric tissues was detected by quantitative real-time PCR and immunohistochemistry. The regulation of IL-32 in human gastric epithelia cell line AGS was investigated by different cytokine stimulation and different H. pylori strain infection.ResultsGastric IL-32 mRNA and protein expression were elevated in patients with H. pylori infection and positively correlated with gastritis. In H. pylori-infected patients, the mRNA level of IL-32 was also correlated with that of proinflammatory cytokines IL-1? and TNF-?. In vitro IL-1? and TNF-? could upregulate IL-32 mRNA and protein level in AGS cells, which was dependent on NF-?B signal pathway. The regulation of IL-32 expression in response to H. pylori-infection could be weakened by using neutralizing antibodies to block IL-1? and TNF-?. Moreover, H. pylori-infected AGS cells also induced IL-32 mRNA and protein expression, which was dependent on CagA.ConclusionsIL-32 level is elevated in patients with H. pylori infection and its expression is regulated by proinflammatory stimuli, suggesting that IL-32 may play a role in the pathogenesis of H. pylori-related gastritis.
| S-EPMC3954549 | biostudies-literature
Project description:It is unclear whether the ability of the innate immune system to recognize distinct ligands from a single microbial pathogen via multiple pattern recognition receptors (PRRs) triggers common pathways or differentially triggers specific host responses. In the human mycobacterial infection leprosy, we found that activation of monocytes via nucleotide-binding oligomerization domain-containing protein 2 (NOD2) by its ligand muramyl dipeptide, as compared to activation via heterodimeric Toll-like receptor 2 and Toll-like receptor 1 (TLR2/1) by triacylated lipopeptide, preferentially induced differentiation into dendritic cells (DCs), which was dependent on a previously unknown interleukin-32 (IL-32)-dependent mechanism. Notably, IL-32 was sufficient to induce monocytes to rapidly differentiate into DCs, which were more efficient than granulocyte-macrophage colony-stimulating factor (GM-CSF)-derived DCs in presenting antigen to major histocompatibility complex (MHC) class I-restricted CD8(+) T cells. Expression of NOD2 and IL-32 and the frequency of CD1b(+) DCs at the site of leprosy infection correlated with the clinical presentation; they were greater in patients with limited as compared to progressive disease. The addition of recombinant IL-32 restored NOD2-induced DC differentiation in patients with the progressive form of leprosy. In conclusion, the NOD2 ligand-induced, IL-32-dependent DC differentiation pathway contributes a key and specific mechanism for host defense against microbial infection in humans.
| S-EPMC3348859 | biostudies-literature