CD40 Activates NF-κB and c-Jun N-Terminal Kinase and Enhances Chemokine Secretion on Activated Human Hepatic Stellate Cells

Schwabe, Robert F.; Schnabl, Bernd; Kweon, Young Oh; Brenner, David A.

doi:10.4049/jimmunol.166.11.6812

Cited by 150 publications

(126 citation statements)

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“…NF-B is activated by CD40 and other members of the TNFR family and has a potentially important function in regulating inflammation (Schwabe et al, 2001) and apoptosis (Foo and Nolan, 1999). In addition, NF-B is critical for regulating liver regeneration and development (Iimuro et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Differential Induction of Nuclear Factor-κB and Activator Protein-1 Activity after CD40 Ligation Is Associated with Primary Human Hepatocyte Apoptosis or Intrahepatic Endothelial Cell Proliferation

Choudhury

Russell

Randhawa

et al. 2003

MBoC

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CD40, a tumor necrosis factor receptor superfamily member, is up-regulated on intraheptatic endothelial cells (IHEC) and epithelial cells during inflammatory liver disease, and there is evidence that the functional outcome of CD40 ligation differs between cell types. Ligation of CD40 on cholangiocytes or hepatocytes results in induction of Fas-mediated apoptosis, whereas ligation of IHEC CD40 leads to enhanced chemokine secretion and adhesion molecule expression. We now report that differential activation of two transcription factors, nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), in primary human hepatocytes or IHEC, is associated with and may explain, in part, the different responses of these cell types to CD40 ligation. CD40 ligation induced a rise in NF-κB activity in hepatocytes ,which peaked at 2 h and returned to baseline by 24 h; however, IHEC CD40 ligation resulted in a sustained up-regulation of NF-κB (>24 h). In hepatocytes, CD40 ligation led to sustained up-regulation of AP-1 activity >24 h associated with increased protein levels of RelA (p65), c-Jun, and c-Fos, whereas no induction of AP-1 activity was observed in IHECs. Analysis of mitogen-activated protein kinase phosphorylation (phospho-extracellular signal-regulated kinase 1/2 and phospho-c-Jun NH2-terminal kinase 1/2) and expression of inhibitor κBα were entirely consistent, and thus confirmed the profiles of NF-κB and AP-1 signaling and the effects of the selective inhibitors assessed using electrophoretic mobility shift assay or Western immunoblotting. CD40 ligation resulted in induction of apoptosis in hepatocytes after 24 h, but on IHECs, CD40 ligation resulted in proliferation. Inhibition of (CD40-mediated) NF-κB activation prevented IHEC proliferation and led to induction of apoptosis. Selective extracellular signal-regulated kinase and c-Jun NH2-terminal kinase inhibitors reduced levels of apoptosis in (CD40-stimulated) hepatocytes by ∼50%. We conclude that differential activation of these two transcription factors in response to CD40 ligation is associated with differences in cell fate. Transient activation of NF-κB and sustained AP-1 activation is associated with apoptosis in hepatocytes, whereas prolonged NF-κB activation and a lack of AP-1 activation in IHECs result in proliferation.

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Section: Discussionmentioning

confidence: 99%

Differential Induction of Nuclear Factor-κB and Activator Protein-1 Activity after CD40 Ligation Is Associated with Primary Human Hepatocyte Apoptosis or Intrahepatic Endothelial Cell Proliferation

Choudhury

Russell

Randhawa

et al. 2003

MBoC

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“…After 2 days in culture, HSCs from normal human liver had a quiescent phenotype, and after 14 days, the HSCs had an activated phenotype as described. 29 The human monocytic cell line THP-1 (from American Type Culture Collection) was cultured in RPMI medium with 10% FCS. THP-1 cells were differentiated by treatment with 10 ng/ml of PMA for 18 h.…”

Section: Activated Human Hsc Cell Line (Htert) and Primary Human Hsc mentioning

confidence: 99%

“…29 Forty micrograms of protein were electrophoresed on 10% SDS-polyacrylamide gels. The gels were then blotted onto a nitrocellulose membrane.…”

Section: Western-blot Analysismentioning

confidence: 99%

“…Rabbit anti-human fibulin-2 (Santa Cruz Biotechnology, Santa Cruz, CA), rabbit anti-human type I collagen (Biodesign, Saco, ME), mouse antihuman a smooth muscle actin (a-SMA) (Dako, Glostrup, Denmark), rabbit anti-human TLR2 (eBioscience, San Diego, CA), rabbit anti-human CD14 (Santa Cruz Biotechnology), and mouse antihuman b-actin (Abcam, Cambridge, MA) antibodies, all diluted 1:1000, were used to detect immunoreactive fibulin-2, type I collagen, a-SMA, TLR2, CD14, and b-actin, respectively, using an enhanced chemiluminescence light (ECL) detecting kit (Amersham Pharmacia Biotech, Piscataway, NJ) as previously described. 29 JAR cell lysate (Santa Cruz Biotechnology) was used as a positive control for fibulin-2.…”

Section: Western-blot Analysismentioning

confidence: 99%

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Hepatic stellate cells primed with cytokines upregulate inflammation in response to peptidoglycan or lipoteichoic acid

Paik

Lee

et al. 2006

Laboratory Investigation

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Gram-positive bacterial products such as peptidoglycan (PGN) and lipoteichoic acid (LTA) are potent stimulators of innate inflammatory responses. We previously reported that lipopolysaccharide (LPS), a major biologically active agent of gram-negative bacteria, induces a proinflammatory response via the Toll-like receptor (TLR) 4 in hepatic stellate cells (HSCs). Here we investigated the mechanism of proinflammatory action by PGN and LTA in activated human HSCs. Following treatment with either TNF-a or IL-1b, expression of TLR2 and CD14 was determined by real-time PCR and Western blotting. NF-jB activation was assessed by NF-jBdriven luciferase assay and electrophoretic mobility shift assay. Interleukin-8 (IL-8) from culture supernatant was measured by ELISA. Activated human HSCs express TLR2 and CD14, which are receptors for PGN and LTA signaling. TNF-a and IL-1b significantly upregulated the expression of TLR2 mRNA and protein in HSCs. PGN and LTA induced NF-jB activation and stimulated production of IL-8 in HSCs. Pretreatment with TNF-a or IL-1b augmented NF-jB activation and IL-8 production in response to PGN or LTA. Both PGN-and LTA-induced NFjB activation and IL-8 secretion were completely inhibited by anti-TLR2 blocking antibody (T2.5). These findings suggest that TNF-a or IL-1b primed HSCs enhance the production of IL-8 in response to PGN and LTA through augmentation of the TLR2 system.

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“…Les cellules étoilées du foie et les cellules mésangiales glomérulaires jouent un rôle clé dans la pathologie inflammatoire du foie et du rein, respectivement. Ces cellules expriment le CD40 et répondent au CD154 par une sécrétion de chimiokines [27,28], suggérant que le CD154 pourrait avoir un rôle important dans la pathologie rénale ou hépatique. La place du CD154 dans la réaction inflammatoire est soulignée dans les modèles de souris CD154 -/-, chez qui la réponse inflammatoire à un stimulus antigénique est presque abrogée.…”

Section: Réaction Inflammatoireunclassified

Le CD154 plaquettaire : Une nouvelle interface dans l’hémostase et la réaction inflammatoire

et al. 2005

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Les plaquettes sanguines sont des éléments figurés du sang provenant de la fragmentation du cytoplasme des mégacaryocytes spécialisés dans la formation du clou hémostatique conduisant à l'arrêt du saignement [1][2][3]. La place de la plaquette dans la réaction inflammatoire a fait l'objet de très nombreux travaux que l'on pourrait schématiser en deux axes, l'un reflétant la participation directe des médiateurs pro-inflammatoires stockés dans les plaquettes et libérés lors de leur activation, l'autre les liens indirects entre activation plaquettaire et réaction inflammatoire, via le système du complément, la cascade des kinines, etc. Différen-tes revues ont été publiées concernant plaquettes et réaction inflammatoire, auxquelles nous renvoyons le lecteur [4]. La mise en évidence récente de l'expression du CD154 par les plaquettes a repositionné ces derniè-res dans la coagulation, la réaction inflammatoire et la réponse immunitaire. CD154 : une molécule indispensable à l'activation des lymphocytes BLe couple CD154/CD40 Le CD154 est une glycoprotéine membranaire de 30 kDa à 33 kDa présentant des homologies de séquence avec les molécules de la famille du tumor necrosis factor (TNF). Les protéines membranaires de cette famille sont > Il a récemment été montré que les plaquettes sanguines exprimaient le CD154 (ligand du CD40), qu'elles extériorisent à leur surface lors de leur activation. Cette découverte a eu des consé-quences importantes sur la compréhension de la biologie de la plaquette. D'une part, le CD154 intervient dans la stabilisation du thrombus plaquettaire. D'autre part, l'interaction des plaquettes avec les cellules exprimant le récepteur CD40 a mis en évidence de nouvelles interfaces liant les plaquettes à la réaction inflammatoire, la coagulation et le remodelage de la matrice extracellulaire. Cela est tout particulièrement vrai pour les interactions plaquettes/vaisseaux et le CD154 plaquettaire joue un rôle clé dans la maladie athéromateuse. Enfin, l'expression du CD154 confère aux plaquettes une compé-tence immunologique, leur faisant jouer un rôle potentiel dans la réponse immune ou dans les pathologies associées à une auto-immunisation antiplaquettaire comme le purpura thrombopé-nique idiopathique. Article disponible sur le site

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CD40 Activates NF-κB and c-Jun N-Terminal Kinase and Enhances Chemokine Secretion on Activated Human Hepatic Stellate Cells

Cited by 150 publications

References 54 publications

Differential Induction of Nuclear Factor-κB and Activator Protein-1 Activity after CD40 Ligation Is Associated with Primary Human Hepatocyte Apoptosis or Intrahepatic Endothelial Cell Proliferation

Differential Induction of Nuclear Factor-κB and Activator Protein-1 Activity after CD40 Ligation Is Associated with Primary Human Hepatocyte Apoptosis or Intrahepatic Endothelial Cell Proliferation

Hepatic stellate cells primed with cytokines upregulate inflammation in response to peptidoglycan or lipoteichoic acid

Le CD154 plaquettaire : Une nouvelle interface dans l’hémostase et la réaction inflammatoire

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