Intracellular Interaction of Interleukin (IL)-32α with Protein Kinase Cϵ (PKCϵ) and STAT3 Protein Augments IL-6 Production in THP-1 Promonocytic Cells

Kang, Jeong Woo; Park, Yun Sun; Lee, Dong Hun; Kim, Jung-hee; Kim, Man Sub; Bak, Yesol; Jiang, Hong; Yoon, Do‐Young

doi:10.1074/jbc.m112.400911

Cited by 53 publications

(85 citation statements)

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“…In this study, we solved our previous question by revealing the mechanism by which IL-32␤ promotes IL-10 production. Recently, several studies have shown the intracellular mediatory function of IL-32 (7,8,33). We demonstrated that IL-32␤ mediated the phosphorylation of serine 21 on C/EBP␣ by PMA-activated PKC␦, which resulted in IL-10 production.…”

Section: Discussionmentioning

confidence: 82%

“…cDNAs for PKC␣, PKC␦, PKC⑀, and PKC were subcloned into the pcDNA3.1 ϩ 5ϫFLAG vector by using EcoRI and XhoI (7). Human intronless C/EBP␣ gene was PCR-amplified from THP-1 genomic DNA by using two overlapping primer sets to obtain the entire cDNA; PCR was then conducted again using the two-PCR fragment as templates.…”

Section: Methodsmentioning

confidence: 99%

“…However, the majority of protein is detected in cellular lysates rather than in the supernatants (2, 4 -6). Recently, the interactions of IL-32 with intracellular proteins, such as focal adhesion kinase 1 (FAK 1), paxillin, integrins, protein kinase C␦ (PKC␦), protein kinase C⑀ (PKC⑀), and STAT3, have been demonstrated, which implies that IL-32 may participate in inflammatory responses as an intracellular mediator (7)(8)(9).…”

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confidence: 99%

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Interleukin (IL)-32β-mediated CCAAT/Enhancer-binding Protein α (C/EBPα) Phosphorylation by Protein Kinase Cδ (PKCδ) Abrogates the Inhibitory Effect of C/EBPα on IL-10 Production

Kang

Park

Kim

et al. 2013

Journal of Biological Chemistry

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Background: IL-32␤ promotes IL-10 production in myeloid cells. Results: IL-32␤-mediated C/EBP␣ serine 21 phosphorylation by PKC␦ induced the dissociation of C/EBP␣ from IL-10 promoter, thereby promoting IL-10 production. Conclusion: IL-32␤ suppressed the inhibitory effect of C/EBP␣ on IL-10 production by mediating C/EBP␣ serine 21 phosphorylation by PKC␦. Significance: Our data suggest that IL-32␤ functions as an intracellular regulator of IL-10 production.

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Section: Discussionmentioning

confidence: 82%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Interleukin (IL)-32β-mediated CCAAT/Enhancer-binding Protein α (C/EBPα) Phosphorylation by Protein Kinase Cδ (PKCδ) Abrogates the Inhibitory Effect of C/EBPα on IL-10 Production

Kang

Park

Kim

et al. 2013

Journal of Biological Chemistry

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“…IL-32α has been reported as the most abundant transcript and the IL-32γ isoform as the longest transcript with most prominent biological activity [13]. Apart from the proinflammatory role of IL-32, the association of IL-32α with PKCε and STAT3 [14] or with FAK1 has been reported [15], suggesting a possible role of this cytokine as an intracellular signaling mediator. Furthermore, the role of IL-32 in the production of regulatory cytokines has been described: IL-32β interacts with PKCδ and C/EBPα, which results in the production of IL-10 [16], and IL-32γ is correlated with enhanced production of proinflammatory cytokines, such as IL-1β and IL-6 [17].…”

Section: Introductionmentioning

confidence: 99%

IL32 expression in peripheral blood CD3+ cells from myelodysplastic syndromes patients

et al. 2017

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Background: Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders characterized by ineffective hematopoiesis and risk of leukemia transformation. There is evidence to suggest the participation of immune system deregulation in MDS pathogenesis. Interleukin-32 (IL-32) is a newly described multifunctional cytokine reported as an important mediator in autoimmune and inflammatory disorders. In the present study, we reported the expression of IL32 and IL32 transcript variants (α, β, γ and δ) in peripheral blood CD3 + cells from healthy controls and MDS patients. Methods: CD3 + cells were isolated by immunomagnetic cell sorting from thirty-nine untreated MDS patients and twenty-nine healthy donors. Gene expression was evaluated by quantitative PCR. For statistical analysis, Mann-Whitney test, Kruskal-Wallis test with Dunns post test and Log-rank (Mantel-Cox) were used, as appropriate. A p value <0.05 was considered statistically significant.

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“…Knockdown of IL-32 decreased TNF-␣, ⌱L-1␤, IL-6, and IL-8 expression in monocytic THP-1 cells and human umbilical cord vein endothelial cells (HUVECs) (26,27). Impressively, upregulation of IL-6 can be enhanced by the interaction between IL-32␣, protein kinase Cε (PKCε), and STAT3 protein in monocytic THP-1 cells (28). In neutrophils, IL-32 can interact with proteinase 3, which may result in the enhancement of IL-32 production to induce IL-8 (29).…”

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confidence: 99%

Maintenance of Epstein-Barr Virus Latent Status by a Novel Mechanism, Latent Membrane Protein 1-Induced Interleukin-32, via the Protein Kinase Cδ Pathway

Lai

Chou

Lin

et al. 2015

J Virol

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Epstein-Barr virus (EBV), an oncogenic herpesvirus, has the potential to immortalize primary B cells into lymphoblastoid cell lines (LCLs) in vitro.During immortalization, several EBV products induce cytokines or chemokines, and most of these are required for the proliferation of LCLs. Interleukin-32 (IL-32), a recently discovered proinflammatory cytokine, is upregulated after EBV infection, and this upregulation is detectable in all LCLs tested. EBV latent membrane protein 1 (LMP1) is responsible for inducing IL-32 expression at the mRNA and protein levels. Mechanistically, we showed that this LMP1 induction is provided by the p65 subunit of NF-B, which binds to and activates the IL-32 promoter. Furthermore, the short hairpin RNA (shRNA)-mediated depletion of endogenous LMP1 and p65 in LCLs suppressed IL-32 expression, further suggesting that LMP1 is the key factor that stimulates IL-32 in LCLs via the NF-B p65 pathway. Functionally, knockdown of IL-32 in LCLs elicits viral reactivation and affects cytokine expression, but it has no impact on cell proliferation and apoptosis. Of note, we reveal the mechanism whereby IL-32 is involved in the maintenance of EBV viral latency by inactivation of Zta promoter activity. This atypical cytoplasmic IL-32 hijacks the Zta activator protein kinase C␦ (PKC␦) and inhibits its translocation from the cytoplasm to the nucleus, where PKC␦ binds to the Zta promoter and activates lytic cycle progression. These novel findings reveal that IL-32 is involved in the maintenance of EBV latency in LCLs. This finding may provide new information to explain how EBV maintains latency, in addition to viral chromatin structure and epigenetic modification. IMPORTANCEEBV persists in two states, latency and lytic replication, which is a unique characteristic of human infections. So far, little is known about how herpesviruses maintain latency in particular tissues or cell types. EBV is an excellent model to study this question because more than 90% of people are latently infected. EBV can immortalize primary B cells into lymphoblastoid cell lines in vitro. Expression of IL-32, a novel atypical cytoplasmic proinflammatory cytokine, increased after infection. The expression of IL-32 was controlled by LMP1. In investigating the regulatory mechanism, we demonstrated that the p65 subunit of NF-B is required for this upregulation. Of note, the important biological activity of IL-32 was to trap protein kinase C␦ in the cytoplasm and prevent it from binding to the Zta promoter, which is the key event for EBV reaction. So, the expression of LMP1-induced IL-32 plays a role in the maintenance of EBV latency. E pstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus: more than 90% of the human population are latently infected (1). Of note, EBV has been reported to be associated with Burkitt's lymphoma (BL), Hodgkin's lymphoma (HL), natural killer (NK)/T-cell lymphoma, AIDS-associated lymphoma, and posttransplantation lymphoproliferative disorder (PTLD) (2). The strongest evidence for EBV onco...

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Intracellular Interaction of Interleukin (IL)-32α with Protein Kinase Cϵ (PKCϵ) and STAT3 Protein Augments IL-6 Production in THP-1 Promonocytic Cells

Cited by 53 publications

References 50 publications

Interleukin (IL)-32β-mediated CCAAT/Enhancer-binding Protein α (C/EBPα) Phosphorylation by Protein Kinase Cδ (PKCδ) Abrogates the Inhibitory Effect of C/EBPα on IL-10 Production

Interleukin (IL)-32β-mediated CCAAT/Enhancer-binding Protein α (C/EBPα) Phosphorylation by Protein Kinase Cδ (PKCδ) Abrogates the Inhibitory Effect of C/EBPα on IL-10 Production

IL32 expression in peripheral blood CD3+ cells from myelodysplastic syndromes patients

Maintenance of Epstein-Barr Virus Latent Status by a Novel Mechanism, Latent Membrane Protein 1-Induced Interleukin-32, via the Protein Kinase Cδ Pathway

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