Affinage

IL32

Interleukin-32 · UniProt P24001

Length
234 aa
Mass
26.7 kDa
Annotated
2026-04-28
100 papers in source corpus 21 papers cited in narrative 21 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IL-32 is a multiisoform proinflammatory cytokine that orchestrates innate and adaptive immune responses, antimicrobial defense, cell death, and metabolic reprogramming through both extracellular signaling and intracellular mechanisms. Extracellularly, IL-32 activates p38 MAPK and NF-κB to induce TNF-α, IL-1β, IL-6, and chemokines in monocytes and macrophages, and signals through integrin αVβ3 via an RGD motif to promote angiogenesis and epithelial–mesenchymal transition (PMID:16492735, PMID:24337385, PMID:30391782); its activity is enhanced by proteolytic processing by proteinase 3, which cleaves IL-32 isoforms into more potent fragments (PMID:16488976, PMID:19017495). Intracellularly, IL-32 restricts viral (HIV-1, VSV, HSV-2) and mycobacterial (M. tuberculosis, M. avium) replication through PKR–eIF-2α, MxA, and IFN-α–dependent pathways and by enhancing phagolysosomal fusion in macrophages (PMID:18566422, PMID:21346229, PMID:25820174, PMID:22033195), while also interacting with mitochondrial respiratory chain components to sustain oxidative phosphorylation and survival in myeloma cells (PMID:35005550). IL-32γ is the most potent proinflammatory isoform and undergoes inflammation-dependent alternative splicing to the less active IL-32β as a negative feedback mechanism, a process subject to allele-specific long-range enhancer regulation that modulates isoform ratios and HIV-1 susceptibility (PMID:21383200, PMID:29507875).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2006 High

    Establishing that IL-32 is an upstream activator of the TNF-α inflammatory cascade resolved how this orphan cytokine connects to canonical inflammation: IL-32γ activates p38 MAPK and NF-κB in macrophages, and its in vivo arthritogenic effect is abolished in TNF-α-knockout mice.

    Evidence Intra-articular injection of IL-32γ in wild-type vs. TNF-α-deficient mice, macrophage and monocyte cytokine assays

    PMID:16492735

    Open questions at the time
    • Receptor identity for p38/NF-κB activation was not identified
    • Upstream signals that induce IL-32 expression were not defined
  2. 2006 High

    Identifying proteinase 3 as both a high-affinity binding partner and an activating protease for IL-32α established the first mechanism for post-translational regulation of IL-32 bioactivity.

    Evidence Affinity chromatography, surface plasmon resonance (Kd ~1–2.65 nM), N-terminal microsequencing, and macrophage cytokine induction assay after PR3 cleavage

    PMID:16488976

    Open questions at the time
    • Whether PR3 processes IL-32 in vivo at inflammatory sites was not shown
    • Other potential processing proteases were not excluded
  3. 2006 Medium

    Demonstrating that intracellular IL-32 promotes activation-induced cell death in T cells revealed a dual extracellular/intracellular mode of action beyond cytokine signaling.

    Evidence Overexpression and siRNA knockdown in HeLa cells with apoptosis rescue readout

    PMID:16410314

    Open questions at the time
    • Intracellular binding partners mediating apoptosis were not identified
    • Relevance to primary T cell AICD was correlative
  4. 2008 High

    Showing that IL-32 restricts HIV-1 replication through NF-κB/AP-1 activation and IFN-α induction linked IL-32 to antiviral innate immunity and defined a functional consequence of its proinflammatory activity.

    Evidence siRNA knockdown in PBMCs and U1 macrophages, p24 HIV-1 production, IFN-α blockade experiments

    PMID:18566422

    Open questions at the time
    • Direct intracellular antiviral mechanism independent of secreted cytokines was not dissected
    • Whether IL-32 restricts HIV at the integration or replication step was unclear
  5. 2010 Medium

    Mapping the upstream inducers of IL-32 isoform expression (TLR2/3/4 ligands, IFN-γ, TNF-α) and showing isoform-selective secretion clarified the positive feedback loop between innate immune activation and IL-32 in rheumatoid arthritis.

    Evidence qRT-PCR, confocal microscopy, ELISA in primary RA fibroblast-like synoviocytes stimulated with TLR ligands and cytokines

    PMID:20615213

    Open questions at the time
    • Mechanisms governing differential secretion vs. intracellular retention of IL-32α were not elucidated
    • Signaling pathways downstream of TLRs to IL-32 transcription were not defined
  6. 2011 High

    Discovering that IL-32γ undergoes inflammation-dependent alternative splicing to the less active IL-32β identified a built-in negative feedback mechanism controlling the potency of the IL-32 inflammatory response.

    Evidence Adenoviral overexpression in THP-1 cells and RA synovial fibroblasts, splice-site mutagenesis preventing γ-to-β conversion, in vivo intra-articular injection

    PMID:21383200

    Open questions at the time
    • Splicing factors mediating the γ-to-β switch were not identified
    • Whether this feedback operates in non-articular tissues was not tested
  7. 2011 Medium

    Extending IL-32's antiviral role beyond HIV, demonstration that IL-32 restricts RNA viruses (VSV) and DNA viruses (HSV-2) via PKR–eIF-2α and MxA pathways, with a substantial IFN-independent component, established IL-32 as a broad innate antiviral effector.

    Evidence siRNA silencing in WISH and Vero cells, viral load quantification, IFN blockade and pathway inhibitor studies

    PMID:21346229

    Open questions at the time
    • Direct physical interaction between IL-32 and PKR or MxA was not demonstrated
    • Relative contribution of IFN-dependent vs. IFN-independent arms was not quantified across virus types
  8. 2013 High

    Identifying integrin αVβ3 as a functional receptor for extracellular IL-32γ resolved a long-standing gap in IL-32 receptor biology and linked IL-32 to angiogenesis, with potency comparable to VEGF in vivo.

    Evidence Co-culture tube formation assay, αVβ3 inhibitor blocking IL-32γ-induced tube formation and IL-8, in vivo Matrigel plug assay, siRNA knockdown in endothelial cells

    PMID:24337385

    Open questions at the time
    • Whether αVβ3 is the sole receptor for IL-32 inflammatory signaling on macrophages was not addressed
    • A second signal (IFN-γ) was required for exogenous responsiveness, and its mechanistic basis was undefined
  9. 2014 Medium

    Systematic mapping of heterodimeric interactions among nine IL-32 isoforms revealed a complex isoform interaction network, raising the possibility that isoform stoichiometry modulates IL-32 bioactivity.

    Evidence Yeast two-hybrid screening identifying 13 interactions, 10 confirmed by reciprocal immunoprecipitation

    PMID:24472437

    Open questions at the time
    • Functional consequences of specific heterodimer pairs on downstream signaling were not tested
    • Whether heterodimers form in vivo at endogenous expression levels is unknown
  10. 2015 High

    In vivo evidence that IL-32γ enhances macrophage killing of M. tuberculosis through phagolysosomal fusion established IL-32 as a cell-autonomous antimycobacterial effector, not merely an upstream inducer of inflammatory cytokines.

    Evidence Transgenic mice expressing human IL-32γ in lung epithelium, aerosol MTB infection with bacterial burden quantification, ex vivo macrophage lysosome colocalization imaging

    PMID:25820174

    Open questions at the time
    • How epithelial IL-32γ signals to alveolar macrophages to enhance phagolysosomal fusion was not defined
    • Whether this mechanism extends to other intracellular pathogens was not tested
  11. 2018 High

    Demonstration that an allele-specific intergenic enhancer (rs4349147) regulates IL-32 isoform ratios via chromatin looping to the promoter, with functional consequences for HIV-1 susceptibility, revealed a cis-regulatory layer controlling IL-32 biology.

    Evidence CRISPR enhancer deletion, chromosome conformation capture (3C), allele-specific clones, RNA-seq, and HIV infection assays in primary CD4+ T cells

    PMID:29507875

    Open questions at the time
    • Transcription factors binding the enhancer element in an allele-specific manner were not identified
    • Whether this regulatory variant influences IL-32 in non-T cell contexts is unknown
  12. 2018 High

    Showing that CAF-derived IL-32 binds integrin β3 via its RGD motif to activate p38 MAPK and EMT in breast cancer cells extended the integrin-mediated signaling axis to tumor invasion and metastasis.

    Evidence siRNA knockdown of IL-32 and integrin β3, p38 MAPK inhibitor, invasion assays, in vivo metastasis model

    PMID:30391782

    Open questions at the time
    • Whether the RGD motif is necessary and sufficient for all integrin-mediated IL-32 functions was not tested across isoforms
    • Contribution of other integrin heterodimers beyond αVβ3 was not excluded
  13. 2021 High

    Discovery that intracellular IL-32 physically interacts with mitochondrial respiratory chain components and is required for oxidative phosphorylation in myeloma cells revealed a metabolic function independent of its cytokine role.

    Evidence CRISPR knockout in three myeloma cell lines, co-immunoprecipitation with mitochondrial components, transcriptomics, MS-based metabolomics, in vivo xenograft

    PMID:35005550

    Open questions at the time
    • Specific respiratory chain subunits bound by IL-32 were not fully characterized structurally
    • Whether this metabolic function operates in non-malignant plasma cells or other cell types is unknown
  14. 2022 Medium

    Two studies showed that IL-32β secreted by tumor cells (via extracellular vesicles or direct secretion) polarizes macrophages toward an immunosuppressive tumor-associated phenotype through FAK–STAT3 and NIK/alternative-NF-κB pathways, establishing IL-32β as a tumor microenvironment modifier.

    Evidence EV isolation and macrophage co-culture with flow cytometry and in vivo metastasis model (ESCC); ex vivo primary MCL–monocyte co-culture with BAFF ELISA and NIK inhibitor (MCL)

    PMID:35263985 PMID:35428295

    Open questions at the time
    • Whether IL-32β-driven macrophage polarization is reversible upon IL-32 neutralization in established tumors is untested
    • Receptor on macrophages mediating IL-32β uptake/signaling in these contexts is not definitively identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the primary signaling receptor on monocytes/macrophages (beyond integrin αVβ3), the structural basis of isoform-specific activity differences, and whether the metabolic function of intracellular IL-32 generalizes beyond myeloma.
  • No high-resolution structure of any IL-32 isoform or IL-32–receptor complex exists
  • A canonical cell-surface receptor mediating NF-κB/p38 activation on myeloid cells has not been identified
  • In vivo isoform-specific knockout models are lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 5 GO:0005829 cytosol 2 GO:0005739 mitochondrion 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-168256 Immune System 5 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-1430728 Metabolism 1
Partners
CXCR1ITGAVITGB3PRTN3TNF

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Proteinase 3 (PR3), a neutrophil granule serine protease, was identified as a specific IL-32α binding protein with high affinity (Kd ~1–2.65 nM), isolated by IL-32α affinity chromatography and confirmed by surface plasmon resonance and N-terminal microsequencing. Limited cleavage of IL-32α by PR3 enhanced cytokine activity (MIP-2 and IL-8 induction), demonstrating that PR3 acts as both a binding partner and a processing enzyme for IL-32. Affinity chromatography, surface plasmon resonance, mass spectrometry, N-terminal microsequencing, in vitro macrophage/PBMC cytokine induction assay Proceedings of the National Academy of Sciences of the United States of America High 16488976
2006 IL-32 activates the p38 MAPK and NF-κB pathways to induce pro-inflammatory cytokines (TNFα, IL-1β, IL-6, chemokines) in monocytes/macrophages, and intra-articular injection of IL-32γ in mice caused joint swelling and inflammatory cell influx that was absent in TNFα-deficient mice, placing IL-32 upstream of TNFα in the inflammatory cascade. In vivo intra-articular injection in wild-type and TNFα-knockout mice, immunohistochemistry, PGE2 release assay in mouse macrophages and human monocytes Proceedings of the National Academy of Sciences of the United States of America High 16492735
2006 IL-32 is involved in activation-induced cell death (AICD) in T cells; enforced intracellular expression of IL-32 induced apoptosis in HeLa cells, and siRNA-mediated knockdown rescued cells from apoptosis, indicating IL-32 can act intracellularly to promote cell death. Overexpression and siRNA knockdown in HeLa cells, apoptosis assays, IL-32 supernatant analysis from apoptotic T cells International immunology Medium 16410314
2008 Endogenous IL-32 in HIV-infected PBMCs activates NF-κB and AP-1 transcription factors to sustain IFN-γ, IL-6, and TNF-α production; siRNA knockdown of IL-32 reduced these cytokines and paradoxically increased HIV-1 p24, revealing that IL-32 restricts HIV-1 replication partly through IFN-α induction. siRNA knockdown in PBMCs and U1 macrophages, NF-κB/AP-1 reporter assays, cytokine protein array, p24 HIV-1 production assay, IFN-α blockade Journal of immunology (Baltimore, Md. : 1950) High 18566422
2008 IL-32 knockdown by siRNA in marrow stromal cells abrogated apoptosis of co-cultured KG1a leukemia cells, demonstrating that stromal IL-32 drives apoptosis of myelodysplastic/leukemic cells; IL-32 also modulates VEGF and other cytokines in marrow stroma. siRNA knockdown in stromal cell lines, co-culture apoptosis assay, cytokine measurement Proceedings of the National Academy of Sciences of the United States of America Medium 18287021
2011 IL-32γ is the most potent proinflammatory isoform; adenoviral overexpression of IL-32γ leads to alternative splicing that produces IL-32β (a less active form) as a negative feedback mechanism. Blocking the splice site by single-nucleotide mutation prevented this conversion and resulted in greater proinflammatory cytokine induction (IL-1β) and markedly enhanced IL-32γ secretion in RA synovial fibroblasts. Adenoviral overexpression in THP1 cells and RA synovial fibroblasts, site-directed mutagenesis of splice site, in vivo intra-articular injection in mice, cytokine ELISA, mRNA analysis Proceedings of the National Academy of Sciences of the United States of America High 21383200
2011 IL-32 restricts replication of RNA viruses (VSV, polyU/polyIC-induced responses) and the DNA virus HSV-2 through the PKR-eIF-2α and MxA antiviral pathways. Silencing endogenous IL-32 nearly abolished polyinosinic-polycytidylic acid-induced IFN-α production in PBMCs; a substantial portion of IL-32's antiviral activity was IFN-independent. siRNA silencing in WISH and Vero cells, lactate dehydrogenase assay for viral load, IFN blockade experiments, pathway inhibitor studies Journal of immunology (Baltimore, Md. : 1950) Medium 21346229
2013 IL-32γ promotes angiogenesis via integrin αVβ3: IL-32γ dose-dependently increased tube formation in co-culture assays (up to 3-fold), and an αVβ3 inhibitor blocked both tube formation and IL-32γ-induced IL-8. In Matrigel plug assays in mice, IL-32γ was as angiogenic as VEGF. siRNA silencing of IL-32 in endothelial cells reduced NO, IL-8, and MMP-9 production without affecting VEGF or apoptosis. A second signal (IFN-γ) was required for exogenous IL-32γ responsiveness. siRNA knockdown in ECs, co-culture tube formation assay, in vivo Matrigel plug assay, αVβ3 inhibitor, EC proliferation assays, synthetic IL-32γ preparation Journal of immunology (Baltimore, Md. : 1950) High 24337385
2013 IL-32γ and IL-32β but not IL-32α induce caspase-8-dependent cell death; IL-32β-induced cell death can be rescued by restoring IL-8/CXCR1 signaling (overexpression of CXCR1), whereas IL-32γ downregulates CXCR1, thereby preventing this rescue and causing cell death. Isoform-specific overexpression in HEK293 cells, caspase-8 assays, CXCR1 overexpression rescue experiment, IL-8 ELISA, analysis in thyroid cancer cell lines Carcinogenesis Medium 26678222
2014 Multiple IL-32 isoforms (α, β, γ, δ, ε, ζ, η, θ, s) form heterodimeric interactions with each other; yeast two-hybrid screening identified 13 heterodimeric interactions and 10 were confirmed by reciprocal immunoprecipitation, establishing an isoform interaction network. Yeast two-hybrid assay, reciprocal immunoprecipitation Biochimie Medium 24472437
2015 IL-32γ (but not IL-32β) enhances macrophage killing of Mycobacterium tuberculosis in vivo; transgenic mice expressing human IL-32γ in lung epithelium had markedly reduced MTB burden and improved survival. Alveolar macrophages from transgenic mice showed increased colocalization of MTB with lysosomes, indicating enhanced phagolysosomal fusion. Transgenic mouse model (SPC-IL-32γTg), aerosol MTB infection, bacterial burden quantification, ex vivo macrophage infection, lysosome colocalization imaging, immune cell profiling Proceedings of the National Academy of Sciences of the United States of America High 25820174
2018 CAF-derived IL-32 interacts with integrin β3 via its RGD motif on breast cancer cells, activating downstream p38 MAPK signaling, which increases EMT markers (fibronectin, N-cadherin, vimentin) and promotes tumor cell invasion and metastasis. siRNA knockdown of IL-32 or integrin β3, p38 MAPK inhibition, invasion assays, in vivo metastasis model, protein interaction demonstrated via binding specificity of RGD motif Cancer letters High 30391782
2008 Proteinase 3 cleavage of IL-32α and IL-32γ at identified PR3 cleavage sites generates separate domain fragments that are more biologically active than intact isoforms; the N-terminal IL-32γ separate domain showed the highest activity among all tested fragments. Recombinant protein domain design based on PR3 cleavage sites, biological activity assays comparing intact vs. cleaved isoforms BMB reports Medium 19017495
2018 A noncoding intergenic enhancer element (rs4349147) regulates IL-32 expression at ~10 kb distance via chromatin looping to the IL-32 promoter in CD4+ T cells; this interaction is allele-dependent. The rs4349147-G allele promotes transcription of non-α IL-32 isoforms, which create a proinflammatory environment that increases susceptibility to HIV-1 infection. CRISPR deletion of enhancer element, chromosome conformation capture (3C), allele-specific clone generation, RNA sequencing, rIL-32γ treatment and lentiviral overexpression in primary CD4+ T cells, HIV infection assays Science advances High 29507875
2018 IL-32γ reduces lung tumor growth by upregulating TIMP-3 expression through promoter hypomethylation; IL-32γ inhibits DNMT1 binding to the TIMP-3 promoter via the NF-κB pathway, thereby preventing TIMP-3 promoter hypermethylation. NF-κB inhibition reversed this effect. IL-32γ cDNA transfection in lung cancer cells, DNMT1 ChIP assay, NF-κB reporter/inhibitor, in vivo carcinogen-induced lung tumor model in IL-32γ transgenic mice Cell death & disease Medium 29467412
2021 Intracellular IL-32 interacts with components of the mitochondrial respiratory chain to promote oxidative phosphorylation in myeloma cells. IL-32 knockout in three myeloma cell lines reduced cell survival and proliferation in vitro and in vivo, and transcriptomic/metabolomic profiling showed accumulation of lipids, pyruvate precursors, and citrate, indicating impaired mitochondrial metabolism. CRISPR/KO of IL-32 in three myeloma cell lines, co-immunoprecipitation with mitochondrial respiratory chain components, high-throughput transcriptomics, MS-based metabolomics, in vivo xenograft iScience High 35005550
2022 Tumor-derived IL-32β (packaged in extracellular vesicles from ESCC cells) is internalized by macrophages and drives M2 macrophage polarization via the FAK-STAT3 pathway, promoting lung metastasis of esophageal squamous cell carcinoma. EV isolation by ultracentrifugation, TEM, Western blot, co-culture of EV with macrophages, immunofluorescence, flow cytometry, in vivo lung metastasis model, FAK/STAT3 pathway analysis Journal of experimental & clinical cancer research : CR Medium 35428295
2022 IL-32β secreted by mantle cell lymphoma cells polarizes monocytes into tumor-associated macrophages that in turn produce BAFF to support lymphoma cell survival; this IL-32β/BAFF pro-survival axis is driven by NIK/alternative-NF-κB signaling, and NIK inhibition disrupts the axis. Ex vivo co-culture of primary MCL cells (n=23) with monocytes, transcriptomic analysis, multiplex immunohistochemistry, BAFF ELISA, NIK inhibitor treatment, IL-32β stimulation experiments Haematologica Medium 35263985
2010 TLR2, TLR3, and TLR4 ligands as well as IFN-γ and TNF-α induce IL-32 mRNA expression in rheumatoid arthritis fibroblast-like synoviocytes (FLS), with different isoforms (β, γ, δ) secreted extracellularly while IL-32α is retained intracellularly; this demonstrates that innate immune pathways upstream regulate IL-32 isoform-specific expression and secretion. Quantitative RT-PCR, confocal microscopy, ELISA in primary RA FLS stimulated with TLR ligands and cytokines Arthritis research & therapy Medium 20615213
2019 miR-29b-3p suppresses oral squamous cell carcinoma migration and invasion by targeting IL-32, which mediates its oncogenic effects through the AKT signaling pathway. miR-29b-3p overexpression, IL-32 knockdown/target validation, migration and invasion assays, AKT pathway analysis in OSCC cells Journal of cellular and molecular medicine Low 31680452
2015 IL-32 restricts Mycobacterium avium growth within airway epithelial cells (BEAS-2B) and macrophages (THP-1) in a NF-κB-dependent manner; exogenous IL-32γ significantly reduced intracellular M. avium colony-forming units, partly through promotion of apoptosis of infected cells, while siRNA-mediated silencing of IL-32 increased intracellular bacterial recovery. NF-κB inhibitor experiments, siRNA silencing of IL-32 in THP-1, exogenous IL-32γ treatment, intracellular bacterial burden quantification, apoptosis assays International immunology Medium 22033195

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Cancer-associated fibroblast (CAF)-derived IL32 promotes breast cancer cell invasion and metastasis via integrin β3-p38 MAPK signalling. Cancer letters 289 30391782
2006 IL-32, a proinflammatory cytokine in rheumatoid arthritis. Proceedings of the National Academy of Sciences of the United States of America 280 16492735
2000 HGF/NK4, a four-kringle antagonist of hepatocyte growth factor, is an angiogenesis inhibitor that suppresses tumor growth and metastasis in mice. Cancer research 190 11118060
2006 Involvement of IL-32 in activation-induced cell death in T cells. International immunology 177 16410314
1998 Inhibition of tumor growth and invasion by a four-kringle antagonist (HGF/NK4) for hepatocyte growth factor. Oncogene 159 9881707
2001 Inhibition of growth, invasion, and metastasis of human pancreatic carcinoma cells by NK4 in an orthotopic mouse model. Cancer research 138 11606388
2008 IL-32, a novel proinflammatory cytokine in chronic obstructive pulmonary disease. American journal of respiratory and critical care medicine 135 18703789
2006 Proteinase 3 is an IL-32 binding protein. Proceedings of the National Academy of Sciences of the United States of America 124 16488976
2003 NK4 (HGF-antagonist/angiogenesis inhibitor) in cancer biology and therapeutics. Cancer science 124 12824898
2006 Interactions between IL-32 and tumor necrosis factor alpha contribute to the exacerbation of immune-inflammatory diseases. Arthritis research & therapy 114 17078892
2008 Dysregulation of IL-32 in myelodysplastic syndrome and chronic myelomonocytic leukemia modulates apoptosis and impairs NK function. Proceedings of the National Academy of Sciences of the United States of America 111 18287021
2011 Inflammation-dependent secretion and splicing of IL-32{gamma} in rheumatoid arthritis. Proceedings of the National Academy of Sciences of the United States of America 104 21383200
2008 Endogenous IL-32 controls cytokine and HIV-1 production. Journal of immunology (Baltimore, Md. : 1950) 100 18566422
1999 Antagonistic effect of NK4, a novel hepatocyte growth factor variant, on in vitro angiogenesis of human vascular endothelial cells. Clinical cancer research : an official journal of the American Association for Cancer Research 87 10589789
2013 IL-32 promotes angiogenesis. Journal of immunology (Baltimore, Md. : 1950) 81 24337385
2012 IL-32 and IL-17 interact and have the potential to aggravate osteoclastogenesis in rheumatoid arthritis. Arthritis research & therapy 78 23148681
2003 Growth and angiogenesis of human breast cancer in a nude mouse tumour model is reduced by NK4, a HGF/SF antagonist. Carcinogenesis 75 12807719
2018 Insights into the role of IL-32 in cancer. Seminars in immunology 72 29747940
2016 IL-32: A Novel Pluripotent Inflammatory Interleukin, towards Gastric Inflammation, Gastric Cancer, and Chronic Rhino Sinusitis. Mediators of inflammation 71 27143819
2001 NK4, a four-kringle antagonist of HGF, inhibits spreading and invasion of human pancreatic cancer cells. British journal of cancer 70 11259105
2014 Interaction network mapping among IL-32 isoforms. Biochimie 69 24472437
2012 Expression of IL-32 modulates NF-κB and p38 MAP kinase pathways in human esophageal cancer. Cytokine 68 23107826
2000 Nk4, a new HGF/SF variant, is an antagonist to the influence of HGF/SF on the motility and invasion of colon cancer cells. International journal of cancer 66 10699931
2020 Molecular interactions and functions of IL-32. Journal of leukocyte biology 63 32869391
2010 Innate immunity triggers IL-32 expression by fibroblast-like synoviocytes in rheumatoid arthritis. Arthritis research & therapy 61 20615213
2003 Inhibition of intracerebral glioblastoma growth by local treatment with the scatter factor/hepatocyte growth factor-antagonist NK4. Clinical cancer research : an official journal of the American Association for Cancer Research 59 14555533
2002 Targeting angiogenesis and HGF function using an adenoviral vector expressing the HGF antagonist NK4 for cancer therapy. Molecular therapy : the journal of the American Society of Gene Therapy 59 11829525
2002 Antagonistic effect of NK4 on HGF/SF induced changes in the transendothelial resistance (TER) and paracellular permeability of human vascular endothelial cells. Journal of cellular physiology 59 12124772
2005 Mechanisms and significance of bifunctional NK4 in cancer treatment. Biochemical and biophysical research communications 56 15950947
2004 Suppression of tumor metastasis by NK4 plasmid DNA released from cationized gelatin. Gene therapy 55 15103321
2016 Multifacility Outbreak of Middle East Respiratory Syndrome in Taif, Saudi Arabia. Emerging infectious diseases 54 26692003
2002 Intraperitoneal injection of adenovirus-mediated NK4 gene suppresses peritoneal dissemination of pancreatic cancer cell line AsPC-1 in nude mice. Cancer gene therapy 54 12224019
1999 The homeodomain transcription factor NK-4 acts as either a transcriptional activator or repressor and interacts with the p300 coactivator and the Groucho corepressor. The Journal of biological chemistry 53 10531357
2013 The role of IL-32 in cutaneous T-cell lymphoma. The Journal of investigative dermatology 52 24226419
2008 Detection of expressed IL-32 in human stomach cancer using ELISA and immunostaining. Journal of microbiology and biotechnology 52 18852519
2003 The HGF/SF antagonist NK4 reverses fibroblast- and HGF-induced prostate tumor growth and angiogenesis in vivo. International journal of cancer 48 12845672
2001 Expression of HGF/NK4 in ovarian cancer cells suppresses intraperitoneal dissemination and extends host survival. Gene therapy 47 11593357
2008 Hepatocyte growth factor and Met in tumor biology and therapeutic approach with NK4. Proteomics 46 18646008
2015 Alternatively spliced isoforms of IL-32 differentially influence cell death pathways in cancer cell lines. Carcinogenesis 45 26678222
2015 Human IL-32 expression protects mice against a hypervirulent strain of Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences of the United States of America 43 25820174
2013 HGF-MET cascade, a key target for inhibiting cancer metastasis: the impact of NK4 discovery on cancer biology and therapeutics. International journal of molecular sciences 41 23296269
2022 Extracellular vesicle IL-32 promotes the M2 macrophage polarization and metastasis of esophageal squamous cell carcinoma via FAK/STAT3 pathway. Journal of experimental & clinical cancer research : CR 40 35428295
2021 Upregulated IL-32 Expression And Reduced Gut Short Chain Fatty Acid Caproic Acid in People Living With HIV With Subclinical Atherosclerosis. Frontiers in immunology 39 33936102
2016 Proinflammatory isoforms of IL-32 as novel and robust biomarkers for control failure in HIV-infected slow progressors. Scientific reports 39 26978598
2009 IL-32: a newly-discovered proinflammatory cytokine. Journal of biological regulators and homeostatic agents 39 19828090
2008 NK4 gene therapy targeting HGF-Met and angiogenesis. Frontiers in bioscience : a journal and virtual library 39 17981681
2000 Inhibition of HGF/SF-induced breast cancer cell motility and invasion by the HGF/SF variant, NK4. Breast cancer research and treatment 36 10832594
2004 Suppression of tumor growth, invasion and angiogenesis of human gastric cancer by adenovirus-mediated expression of NK4. The journal of gene medicine 35 15026993
2011 IL-32 expression in the airway epithelial cells of patients with Mycobacterium avium complex lung disease. International immunology 34 22033195
2004 Adenoviral-mediated gene transduction of the hepatocyte growth factor (HGF) antagonist, NK4, suppresses peritoneal metastases of gastric cancer in nude mice. European journal of cancer (Oxford, England : 1990) 34 15341989
2002 HGF/NK4 inhibited VEGF-induced angiogenesis in in vitro cultured endothelial cells and in vivo rabbit model. Diabetologia 34 12637990
2014 IL-32 promotes breast cancer cell growth and invasiveness. Oncology letters 33 25435980
2011 Protection from RNA and DNA viruses by IL-32. Journal of immunology (Baltimore, Md. : 1950) 33 21346229
2002 Gene transduction of NK4, HGF antagonist, inhibits in vitro invasion and in vivo growth of human pancreatic cancer. Clinical & experimental metastasis 33 12198770
2015 A panoramic spectrum of complex interplay between the immune system and IL-32 during pathogenesis of various systemic infections and inflammation. European journal of medical research 32 25626592
2014 Mesenchymal stem cell-based NK4 gene therapy in nude mice bearing gastric cancer xenografts. Drug design, development and therapy 32 25525335
2012 Regulation and expression of IL-32 in chronic rhinosinusitis. Allergy 30 22486709
2006 Blockage of HGF/c-Met system by gene therapy (adenovirus-mediated NK4 gene) suppresses hepatocellular carcinoma in mice. Journal of hepatology 30 16839638
2002 Tumor suppression through angiogenesis inhibition by SUIT-2 pancreatic cancer cells genetically engineered to secrete NK4. Clinical cancer research : an official journal of the American Association for Cancer Research 30 12374695
2015 Phosphorylation of CHIP at Ser20 by Cdk5 promotes tAIF-mediated neuronal death. Cell death and differentiation 29 26206088
2006 Enhanced suppression of tumor growth using a combination of NK4 plasmid DNA-PEG engrafted cationized dextran complex and ultrasound irradiation. Cancer gene therapy 29 16276347
2004 Suppression of the progress of disseminated pancreatic cancer cells by NK4 plasmid DNA released from cationized gelatin microspheres. Pharmaceutical research 29 15290849
2013 IL-32 with potential insights into rheumatoid arthritis. Clinical immunology (Orlando, Fla.) 28 23578550
2002 The human tachykinin NK1 (short form) and tachykinin NK4 receptor: a reappraisal. European journal of pharmacology 28 11864635
2006 Peritumoral injection of adenovirus vector expressing NK4 combined with gemcitabine treatment suppresses growth and metastasis of human pancreatic cancer cells implanted orthotopically in nude mice and prolongs survival. Cancer gene therapy 27 16341142
2005 Mast cell and neutrophil peptidases attack an inactivation segment in hepatocyte growth factor to generate NK4-like antagonists. The Journal of biological chemistry 27 16303761
2009 Angioinhibitory action of NK4 involves impaired extracellular assembly of fibronectin mediated by perlecan-NK4 association. The Journal of biological chemistry 26 19553700
2005 Inhibition of angiogenesis and HGF-cMET-elicited malignant processes in human hepatocellular carcinoma cells using adenoviral vector-mediated NK4 gene therapy. Cancer gene therapy 26 15905856
2002 Tumor suppression effect using NK4, a molecule acting as an antagonist of HGF, on human gastric carcinomas. Cancer gene therapy 26 12136432
2015 DNA methylation at IL32 in juvenile idiopathic arthritis. Scientific reports 25 26057774
2011 Association between IL-32 genotypes and outcome in infection-associated acute lung injury. Critical care (London, England) 24 21649914
2015 Important Role of the IL-32 Inflammatory Network in the Host Response against Viral Infection. Viruses 23 26087456
2005 Suppression of metastasis of human pancreatic cancer to the liver by transportal injection of recombinant adenoviral NK4 in nude mice. International journal of cancer 23 15880501
2016 Polymorphisms and expression of IL-32: impact on genetic susceptibility and clinical outcome of lung cancer. Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals 22 27775437
2008 Proteinase 3-processed form of the recombinant IL-32 separate domain. BMB reports 22 19017495
2017 The Inhibitory Effect of Mesenchymal Stem Cells with rAd-NK4 on Liver Cancer. Applied biochemistry and biotechnology 21 28353041
2010 Anti-cancer approach with NK4: Bivalent action and mechanisms. Anti-cancer agents in medicinal chemistry 21 20015005
2004 Reduced HGF expression in subcutaneous CT26 tumor genetically modified to secrete NK4 and its possible relation with antitumor effects. Cancer science 21 15072590
2018 IL-32 gamma reduces lung tumor development through upregulation of TIMP-3 overexpression and hypomethylation. Cell death & disease 20 29467412
2018 Allele-specific long-distance regulation dictates IL-32 isoform switching and mediates susceptibility to HIV-1. Science advances 20 29507875
2016 The hepatocyte growth factor antagonist NK4 inhibits indoleamine-2,3-dioxygenase expression via the c-Met-phosphatidylinositol 3-kinase-AKT signaling pathway. International journal of oncology 20 27082119
2015 TLR3/TRIF signalling pathway regulates IL-32 and IFN-β secretion through activation of RIP-1 and TRAF in the human cornea. Journal of cellular and molecular medicine 20 25754842
2015 Dysregulation of over-expressed IL-32 in colorectal cancer induces metastasis. World journal of surgical oncology 20 25889282
2021 Intracellular IL-32 regulates mitochondrial metabolism, proliferation, and differentiation of malignant plasma cells. iScience 19 35005550
2006 Preclinical study of a "tailor-made" combination of NK4-expressing gene therapy and gefitinib (ZD1839, Iressa) for disseminated peritoneal scirrhous gastric cancer. International journal of cancer 19 16206271
2019 MicroRNA-29b-3p suppresses oral squamous cell carcinoma cell migration and invasion via IL32/AKT signalling pathway. Journal of cellular and molecular medicine 18 31680452
2015 Significant association between IL-32 gene polymorphisms and susceptibility to endometrial cancer in Chinese Han women. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 18 25663496
2007 Inhibition of colon cancer growth and metastasis by NK4 gene repetitive delivery in mice. Biochemical and biophysical research communications 18 17467663
2025 Overcoming immunotherapy resistance in colorectal cancer through nano-selenium probiotic complexes and IL-32 modulation. Biomaterials 17 40081224
2022 Predicting roles of IL-27 and IL-32 in determining the severity and outcome of COVID-19. International journal of immunopathology and pharmacology 17 36476070
2021 IL-32 exacerbates adenoid hypertrophy via activating NLRP3-mediated cell pyroptosis, which promotes inflammation. Molecular medicine reports 17 33495843
2019 Structural Characteristics of Seven IL-32 Variants. Immune network 17 31089435
2008 A human dendritic cell subset receptive to the Venezuelan equine encephalitis virus-derived replicon particle constitutively expresses IL-32. Journal of immunology (Baltimore, Md. : 1950) 17 18768856
2022 The Serum Levels of IL-36 in Patients with Coronary Artery Disease and Their Correlation with the Serum Levels of IL-32, IL-6, TNF-α, and Oxidative Stress. International archives of allergy and immunology 16 35878588
2021 IL32: The multifaceted and unconventional cytokine. Human immunology 16 34024634
2019 Increased expression of IL-32 correlates with IFN-γ, Th1 and Tc1 in virologically suppressed HIV-1-infected patients. Cytokine 16 30910260
2014 IL32 is progressively expressed in mycosis fungoides independent of helper T-cell 2 and helper T-cell 9 polarization. Cancer immunology research 16 24938282
2014 Anti-obesity effects of Taif and Egyptian pomegranates: molecular study. Bioscience, biotechnology, and biochemistry 16 25420097
2008 Unique expression of a small IL-32 protein in the Jurkat leukemic T cell line. Cytokine 16 18289868
2022 The IL32/BAFF axis supports prosurvival dialogs in the lymphoma ecosystem and is disrupted by NIK inhibition. Haematologica 15 35263985