Lipopolysaccharide mediated regulation of neuroendocrine associated proprotein convertases and neuropeptide precursor processing in the rat spleen

Lansac, Guillaume; Dong, Weijia; Dubois, Claire M.; BenLarbi, Nadia; Afonso, Carlos; Fournier, Isabelle; Salzet, Michel; Day, Robert

doi:10.1016/j.jneuroim.2005.09.019

Cited by 32 publications

(28 citation statements)

References 57 publications

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“…We also noted previously that PC1/3 expression in the spleen (16) was mostly confined to the red pulp regions known to be rich in macrophages (28) and was increased after LPS stimulation. Co-localization of PC1/3 with CD14, a macrophage marker (29), sparked our interest in investigating the role of PC1/3 in macrophages to elucidate the function of PC1/3 in the innate immune system.…”

supporting

confidence: 80%

“…However, few studies have provided evidence for PC1/3 expression in non-neuroendocrine cells, including macrophages (14,15). Previous work from our laboratory has demonstrated that PC1/3 expression is regulated by pathogen-associated molecular patterns, specifically LPS, which activates the TLR4 pathway (16). The regulation of the observed expression pattern has encouraged us to explore the PC1/3 KO mouse model from a perspective relating to innate immune mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…In a previous study, we showed that both neuroendocrine-"specific" convertases, namely PC2 and PC1/3, are also expressed in macrophages and lymphocytes in vivo (16) and are highly responsive to pathogen-associated molecular pattern challenge. We also showed a coordinated induction of proenkephalin (a PC1/3 and PC2 substrate), PC1/3, and PC2 mRNAs as well as proenkephalin-derived peptides (i.e.…”

mentioning

confidence: 99%

“…For example, PC1/3 has been associated with the neuroendocrine system where its expression was first reported (11)(12)(13). However, a few studies have identified an atypical expression of PC1/3 in cells of the immune system; namely PC1/3 has been detected in a human monocyte-derived macrophage cell line (14), differentiated macrophages (15), and immune organs, such as the spleen, thymus, and lymphatic ganglia (16).…”

mentioning

confidence: 99%

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Disruption of Proprotein Convertase 1/3 (PC1/3) Expression in Mice Causes Innate Immune Defects and Uncontrolled Cytokine Secretion

Refaie

Gagnon

et al. 2012

Journal of Biological Chemistry

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supporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Disruption of Proprotein Convertase 1/3 (PC1/3) Expression in Mice Causes Innate Immune Defects and Uncontrolled Cytokine Secretion

Refaie

Gagnon

et al. 2012

Journal of Biological Chemistry

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“…PC2 and PC1/3 operate within the regulated secretory pathway. Their expression is not restricted to neuroendocrine tissues, they are also expressed in macrophages and lymphocytes (12). In a previous study from our group, PC1/3 knockout (KO) in mice challenged with LPS caused innate immune defects and uncontrolled cytokine secretion (10).…”

mentioning

confidence: 99%

Molecular Consequences of Proprotein Convertase 1/3 (PC1/3) Inhibition in Macrophages for Application to Cancer Immunotherapy: A Proteomic Study

Duhamel

Rodet

Delhem

et al. 2015

Molecular & Cellular Proteomics

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Macrophages provide the first line of host immune defense. Their activation triggers the secretion of pro-inflammatory cytokines and chemokines recruiting other immune cells. In cancer, macrophages present an M2 anti-inflammatory phenotype promoting tumor growth. In this way, strategies need to be develop to reactivate macrophages. Previously thought to be expressed only in cells with a neural/neuroendocrine phenotype, the proprotein convertase 1/3 has been shown to also be expressed in macrophages and regulated as a function of the Toll-like receptor immune response. Here, we investigated the intracellular impact of the down-regulation of the proprotein convertase 1/3 in NR8383 macrophages and confirmed the results on macrophages from PC1/3 deficient mice. A complete proteomic study of secretomes and intracellular proteins was undertaken and revealed that inhibition of proprotein convertase 1/3 orient macrophages toward an M1 activated phenotype. This phenotype is characterized by filopodial extensions, Tolllike receptor 4 MyD88-dependent signaling, calcium entry augmentation and the secretion of pro-inflammatory factors. In response to endotoxin/lipopolysaccharide, these intracellular modifications increased, and the secreted factors attracted naïve T helper lymphocytes to promote the cytotoxic response. Importantly, the application of these factors onto breast and ovarian cancer cells resulted in a decrease viability or resistance. Under inhibitory conditions using interleukin 10, PC1/3-knockdown macrophages continued to secrete inflammatory factors. These data indicate that targeted inhibition of proprotein convertase 1/3 could represent a novel type of immune therapy to reactivate intra-tumoral macrophages. Molecular & Cellular

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B Lymphocytes Express Pomc mRNA, Processing Enzymes and β-Endorphin in Painful Inflammation

Maddila

Busch-Dienstfertig

Stein

2016

J Neuroimmune Pharmacol

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Immune cell-derived beta-endorphin (END) and other opioid peptides elicit potent and clinically relevant inhibition of pain (analgesia) in inflamed tissue by activation of peripheral opioid receptors. Pro-opiomelanocortin (POMC) is the polypeptide precursor of END and is processed by prohormone convertases (PCs). This study aims to decipher the processing of POMC in lymphocyte subsets in a rat model of unilateral painful hindpaw inflammation. Lymphocytes, isolated from popliteal lymph nodes, were separated into B-cells, T-cells, T-helper cells and cytotoxic T-cells using magnetic cell sorting, and were examined by polymerase chain reaction, immunofluorescence and radioimmunoassay. At 2 h of inflammation, POMC exon 2-3 mRNA was mostly expressed in B- but not in T-cells. Prohormone convertase 1 (PC1) mRNA and protein were upregulated in B-cells and T-helper cells. Prohormone convertase 2 (PC2) was expressed in T- and B-cells, both in inflamed and non-inflamed lymph nodes. END was expressed in B- but not in T-cells. We conclude that POMC, its processing enzymes and END are predominantly expressed in B-lymphocytes at 2 h of paw inflammation.

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Lipopolysaccharide mediated regulation of neuroendocrine associated proprotein convertases and neuropeptide precursor processing in the rat spleen

Cited by 32 publications

References 57 publications

Disruption of Proprotein Convertase 1/3 (PC1/3) Expression in Mice Causes Innate Immune Defects and Uncontrolled Cytokine Secretion

Disruption of Proprotein Convertase 1/3 (PC1/3) Expression in Mice Causes Innate Immune Defects and Uncontrolled Cytokine Secretion

Molecular Consequences of Proprotein Convertase 1/3 (PC1/3) Inhibition in Macrophages for Application to Cancer Immunotherapy: A Proteomic Study

B Lymphocytes Express Pomc mRNA, Processing Enzymes and β-Endorphin in Painful Inflammation

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