Lipopolysaccharide Up-regulates IL-6Rα Expression in Cultured Leptomeningeal Cells via Activation of ERK1/2 Pathway

Wang, Ting; Wang, Bai-Ren; Zhao, Hongyu; Kuang, Fang; Fan, Juan; Duan, Xingwu; Ju, Gong

doi:10.1007/s11064-008-9667-z

Cited by 10 publications

(4 citation statements)

References 54 publications

(55 reference statements)

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“…This effect of TGF-b might be independent of IL-6, as we showed that IL-1b increased IL-6 production but did not affect IL-6R expression. In literature, inflammatory factors such as LPS and IL-1b are mainly known to increase IL6R expression 36,37 . However, this seems to be cell type specific as IL-1b decreases IL6R expression in monocytes, but increases its levels in hepatocytes 38 .…”

Section: Discussionmentioning

confidence: 99%

TGF-β dampens IL-6 signaling in articular chondrocytes by decreasing IL-6 receptor expression

Wiegertjes

Caam

Beuningen

et al. 2019

Osteoarthritis and Cartilage

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Objective: Transforming growth factor-b (TGF-b) is an important homeostatic regulator of cartilage. In contrast, interleukin-6 (IL-6) is a pro-inflammatory cytokine implicated in cartilage degeneration. Crosstalk between TGF-b and IL-6 is reported in tissues other than articular cartilage. Here, we investigated regulation of IL-6 signaling by TGF-b in articular chondrocytes. Design: Human primary chondrocytes and the human G6 chondrocyte cell line were stimulated with TGF-b1 or interleukin-1b (IL-1b). Expression of IL-6 and IL-6 receptor (IL-6R) was determined on mRNA and protein level. TGF-b regulation of IL-6 signaling via phosho-STAT3 (p-STAT3) was determined using Western blot, in presence of inhibitors for IL-6R, and Janus kinase(JAK)-and activin receptor-like kinase ALK)5 kinase activity. Furthermore, induction of STAT3-responsive genes was used as a read-out for IL-6 induced gene expression. Results: TGF-b1 increased IL-6 mRNA and protein expression in both G6 and primary chondrocytes. Moreover, TGF-b1 stimulation clearly induced p-STAT3), which was abolished by inhibition of either IL-6R, JAK-or ALK5 kinase activity. However, TGF-b1 did not increase expression of the STAT3-responsive gene SOCS3 and pre-treatment with TGF-b1 even inhibited induction of p-STAT3 and SOCS3 by rhIL-6. Interestingly, TGF-b1 potently decreased IL-6R expression. In contrast, IL-1b did increase IL-6 levels, but did not affect IL-6R expression. Finally, addition of recombinant IL-6R abolished the inhibitory effect of TGF-b1 on IL-6-induced p-STAT3 and downstream SOCS3, BCL3, SAA1 and MMP1 expression. Conclusions: In this study we show that TGF-b decreases IL-6R expression, thereby dampening IL-6 signaling in chondrocytes. This reveals a novel effect of TGF-b, possibly important to restrict proinflammatory IL-6 effects to preserve cartilage homeostasis.

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Section: Discussionmentioning

confidence: 99%

TGF-β dampens IL-6 signaling in articular chondrocytes by decreasing IL-6 receptor expression

Wiegertjes

Caam

Beuningen

et al. 2019

Osteoarthritis and Cartilage

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“…The leptomeninges were always thought to be in the front line against infections to defend the CNS [ 9 , 10 ], whereas meninges serve not only as a physical defense against infectious molecules, but also involve in signal transmission [ 11 ], molecule transport [ 12 ], stem cell incubation [ 11 ], and the immune responses in brain-resident inflammatory cells in the CNS [ 13 ]. Further evidence [ 14 ] shows that many substances, receptors, and cytokines, such as LPS, interleukin-1 β (IL-1 β ), interleukin-6 (IL-6), cyclooxygenase (COX)-2, I κ B α , tumor necrosis factor α (TNF- α ), and prostaglandin (PG), pronouncedly enhance secretion of more inflammatory factors from leptomeningeal cells. That means cytokines coming from leptomeningeal cells have been activated in the CNS even before the imminent entry of P. gingivalis into the brain.…”

Section: Introductionmentioning

confidence: 99%

Coniferyl Aldehyde Inhibits the Inflammatory Effects of Leptomeningeal Cells by Suppressing the JAK2 Signaling

Wang

Gao

et al. 2020

BioMed Research International

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Background. The brain is in many ways an immunologically and pharmacologically privileged site because of the blood-brain barrier (BBB). But for chronic peripheral inflammation, inflammatory signals can be transmitted from the peripheral system into the central nervous system (CNS) through multiple channels and result in neuroinflammation. Leptomeningeal cells that form the BBB can trigger one signaling pathway by releasing cytokines to transmit inflammatory signals. Besides, the Janus kinase (JAK) family may have a certain function in the activation of leptomeninges. In the present study, we try to use coniferyl aldehyde (CA), a natural anti-inflammatory phenolic compound, to inhibit this inflammatory process and elucidate the underlying molecular mechanisms. Results. Secretion of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) significantly increased after incubation with P. gingivalis. Moreover, TNF-α, IL-1β, and IL-6 levels were upregulated, and the JAK2 signaling was enhanced in leptomeningeal cells in a conditioned medium from activated macrophages, which leads to the immune response in microglia. However, this inflammatory effect of leptomeningeal cells was reversed by CA administration, accompanied by the decreased immune response in microglia. The western blot assay revealed that JAK2 phosphorylation was suppressed in leptomeningeal cells treated with CA. Conclusions. This study demonstrates that activated macrophages by P. gingivalis markedly induce the release of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) from leptomeningeal cells, thereby activating the JAK2 signaling pathway and subsequently enhancing immune responses in microglia in the CNS. CA effectively inhibits the inflammatory effect of leptomeningeal cells via suppressing the JAK2 signaling pathway.

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“…The changes of expression CAPON can affect cardiac re-polarization and the QT interval [18] . LPS-stimulated cells over-expressed inflammatory mediators such as pro-inflammatory cytokines, cyclooxygenase-2, MMP-9 and NOS [21,22] . In the present study, we found that the expression levels of CAPON transcripts and protein expressed in a dosedependent manner in inflammatory rat brain after LPS stimulation.…”

Section: Discussionmentioning

confidence: 99%

The Nuclear Localization of CAPON in Hippocampus and Cerebral Cortex Neurons after Lipopolysaccharide Stimulation

Shao

Jiang²,

Wu³

et al. 2010

Neuroimmunomodulation

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Objective: In the brain, nitric oxide (NO) is a retrograde signalling molecule that transfers information from post- to pre-synaptic nerve endings. NO has been shown to be an important inflammatory mediator responding to lipopolysaccharide (LPS). It has been stated that the constitutive NO synthase isoforms (nNOS and eNOS) may also contribute to the inflammation. CAPON, a nNOS regulator, helps regulate nNOS stability, localization and possibly expression during synapse formation as well as muscle re-innervation. Recently, it has been reported that CAPON is associated with psychiatric illness. So we speculated that the CAPON expression-induced physiological changes may be mediated by modifications of NOS-NO signalling pathways. But little is known about the role of CAPON during the inflammation in the central nervous system, so we investigated the expression of CAPON in the brain treated with LPS. Methods and Results: Real-time PCR and Western blot showed that the expression of CAPON increased at mRNA and protein levels in the brain after LPS stimulation. Immunocytochemistry staining revealed that CAPON localized in the nuclei of neurons in the brain after peritoneal injection with LPS in vivo. The same phenomenon was also shown in primary cultured neurons in vitro incubated with LPS for 36 h. In addition, we found that CAPON had a colocalization with phosphorylated nNOS Ser847 but not with nNOS in hippocampus and cerebral cortex by double immunofluorescence. Conclusion: CAPON localized in the nuclei of neurons in hippocampus and cerebral cortex after LPS treatment. Because CAPON competed with PSD-95 for binding nNOS in neurons and nNOS was activated to produce NO through the NMDA- NMDAR pathway, we hypothesized that CAPON might play a proactive role in the process of inflammation by transferring from cytoplasm to the nucleus and through the NMDA-nNOS signal pathway. Further studies are required to clarify the mechanism of the nuclear localization of CAPON and the possible relationship with nNOS/NO signalling.

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Lipopolysaccharide Up-regulates IL-6Rα Expression in Cultured Leptomeningeal Cells via Activation of ERK1/2 Pathway

Cited by 10 publications

References 54 publications

TGF-β dampens IL-6 signaling in articular chondrocytes by decreasing IL-6 receptor expression

TGF-β dampens IL-6 signaling in articular chondrocytes by decreasing IL-6 receptor expression

Coniferyl Aldehyde Inhibits the Inflammatory Effects of Leptomeningeal Cells by Suppressing the JAK2 Signaling

The Nuclear Localization of CAPON in Hippocampus and Cerebral Cortex Neurons after Lipopolysaccharide Stimulation

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