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, Jeong Woo; Park, Yun Sun; Kim, Man Sub; Lee, Dong Hun; Bak, Yesol; Ham, Sun Young; Park, Soo Ho; Hong, Jin Tae; Yoon, Do‐Young

doi:10.1074/jbc.m113.465575

Cited by 26 publications

(45 citation statements)

References 34 publications

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“…Three isoforms of IL-32 (η, θ, s) were recently identified by our group [12]. The IL-32α and IL-32β isoforms are the most abundant in A549 lung cancer cells and U937 myeloid lymphoma cells, respectively, whereas IL-32ε and IL-32ζ are both expressed in T cells [9,13,14]. IL-32 has bifunctional effects on the immune response in that it can induce the expression of not only pro-inflammatory cytokines, including tumor necrosis factor α (TNF-α) and IL-1β [6], but also the anti-inflammatory cytokine, IL-10 [15].…”

Section: Introductionmentioning

confidence: 98%

IL-32θ downregulates CCL5 expression through its interaction with PKCδ and STAT3

Bak

Kang

Kim

et al. 2014

Cellular Signalling

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Section: Introductionmentioning

confidence: 98%

IL-32θ downregulates CCL5 expression through its interaction with PKCδ and STAT3

Bak

Kang

Kim

et al. 2014

Cellular Signalling

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“…Rottlerin has generally been used as a specific inhibitor for PKCδ (Gschwendt et al, 1994;Kang et al, 2013). However, our previous Control, n=46 cells (four slices); Jnk1-sh788, n=49 cells (five slices); Jnk1-sh788+wt-Jnk1, n=58 cells (five slices).…”

Section: Jnk Regulates Nuclear Elongation But Not Dilation Formationmentioning

confidence: 99%

Cdk5 and its substrates, Dcx and p27kip1, regulate cytoplasmic dilation formation and nuclear elongation in migrating neurons

et al. 2014

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Neuronal migration is crucial for development of the mammalian-specific six-layered cerebral cortex. Migrating neurons are known to exhibit distinct features; they form a cytoplasmic dilation, a structure specific to migrating neurons, at the proximal region of the leading process, followed by nuclear elongation and forward movement. However, the molecular mechanisms of dilation formation and nuclear elongation remain unclear. Using ex vivo chemical inhibitor experiments, we show here that rottlerin, which is widely used as a specific inhibitor for PKCδ, suppresses the formation of a cytoplasmic dilation and nuclear elongation in cortical migrating neurons. Although our previous study showed that cortical neuronal migration depends on Jnk, another downstream target of rottlerin, Jnk inhibition disturbs only the nuclear elongation and forward movement, but not the dilation formation. We found that an unconventional cyclin-dependent kinase, Cdk5, is a novel downstream target of rottlerin, and that pharmacological or knockdown-mediated inhibition of Cdk5 suppresses both the dilation formation and nuclear elongation. We also show that Cdk5 inhibition perturbs endocytic trafficking as well as microtubule organization, both of which have been shown to be required for dilation formation. Furthermore, knockdown of Dcx, a Cdk5 substrate involved in microtubule organization and membrane trafficking, or p27 kip1 , another Cdk5 substrate involved in actin and microtubule organization, disturbs the dilation formation and nuclear elongation. These data suggest that Cdk5 and its substrates, Dcx and p27 kip1 , characterize migrating neuronspecific features, cytoplasmic dilation formation and nuclear elongation in the mouse cerebral cortex, possibly through the regulation of microtubule organization and an endocytic pathway.

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“…Recently, Kang et al demonstrated that IL-32 interacts with PKCε and STAT3 to induce IL-6 expression in monocytic THP-1 cells (28). The interaction of PKC␦, IL-32, and C/EBP␣ suppressed the inhibitory effects of C/EBP␣ on the IL-10 promoter in myeloid cells (47). These studies suggested that IL-32 may modulate various functions by interacting with different proteins in different cell types.…”

Section: Discussionmentioning

confidence: 97%

“…5B show that knockdown of IL-32 did not induce PARP or caspase-3 cleavage, suggesting that depletion of IL-32 does not affect apoptosis. Previous studies demonstrated that IL-32 enhances IL-6, IL-8, and IL-10 (29,46,47). In addition, these cytokines have been induced by LMP1 (48)(49)(50).…”

Section: Expression Pattern and Cellular Distribution Of Il-32 Inmentioning

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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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

Cited by 26 publications

References 34 publications

IL-32θ downregulates CCL5 expression through its interaction with PKCδ and STAT3

IL-32θ downregulates CCL5 expression through its interaction with PKCδ and STAT3

Cdk5 and its substrates, Dcx and p27kip1, regulate cytoplasmic dilation formation and nuclear elongation in migrating neurons

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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