CD40 Activates NF-κB and c-Jun N-Terminal Kinase and Enhances Chemokine Secretion on Activated Human Hepatic Stellate Cells
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Activated hepatic stellate cells (HSCs) are the main producers of extracellular matrix in the fibrotic liver and contribute to hepatic inflammation through the secretion of chemokines and the recruitment of leukocytes. This study assesses the function of CD40 on human HSCs. Activated human HSCs express CD40 in culture and in fibrotic liver, as determined by flow cytometry, RT-PCR, and immunohistochemistry. CD40 expression is strongly enhanced by IFN-γ. Stimulation of CD40 with CD40 ligand (CD40L)-transfected baby hamster kidney cells induces NF-κB, as demonstrated by the activation of I-κB kinase (IKK), increased NF-κB DNA binding, and p65 nuclear translocation. CD40-activated IKK also phosphorylates a GST-p65 substrate at serine 536 in the transactivation domain 1. Concomitant with the activation of IKK, CD40L-transfected baby hamster kidney cell treatment strongly activates c-Jun N-terminal kinase. CD40 activation increases the secretion of IL-8 and monocyte chemoattractant protein-1 by HSCs 10- and 2-fold, respectively. Adenovirally delivered dominant negative (dn) IKK2 and TNFR-associated factor 2dn inhibit IKK-mediated GST-I-κB and GST-p65 phosphorylation, NF-κB binding, and IL-8 secretion, whereas IKK1dn and NF-κB-inducing kinase dominant negative do not have inhibitory effects. We conclude that the CD40-CD40L receptor-ligand pair is involved in a cross-talk between HSCs and immune effector cells that contributes to the perpetuation of HSC activation in liver fibrosis through TNFR-associated factor 2- and IKK2-dependent pathways.
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Activated HSCs recruit immune cells by secreting chemokines including MCP-1, IL-8, RANTES, CCR5, and SDF-1/CXCL-12 and express adhesion molecules ICAM-1 and VCAM-1 that promote infiltration of leukocytes and macrophages.
“Activated HSCs recruit immune cells by secreting numerous chemokines including monocyte chemoattractant protein-1 (MCP-1) (34), IL-8 (35), RANTES and CCR5 (36), and SDF-1/CXCL-12 (37) and express adhesion molecules, ICAM-1 and VCAM-1, that promote the infiltration of leukocytes and macrophages (38, 39).”
From Hepatic Stellate Cell-Immune Interactions in NASH (2022) · cites this paper as [35]
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Hepatic Stellate Cell-Immune Interactions in NASH
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- Authors
- Schwabe, R. F., Schnabl, B., Kweon, Y. O., & Brenner, D. A.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2001-06-01
- Volume
- 166
- Issue
- 11
- Pages
- 6812-6819
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1535684553
- Cited by
- 155
- References
- 51
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 4 · 2023: 6 · 2022: 2 · 2021: 2 · 2019: 3 · 2018: 2 · 2017: 8 · 2016: 6 · 2015: 7 · 2014: 5 · 2013: 6 · 2012: 5
- FWCI
- 8.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Liver Foundation
- Deutsche Forschungsgemeinschaft
- National Institutes of Health (DK-34987)
- National Institute of General Medical Sciences (GM41804, R01GM041804)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 34987, P30DK034987)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- CD40, CD40 ligand, hepatic stellate cells, NF-κB, c-Jun N-terminal kinase, IκB kinase, liver fibrosis, chemokine secretion, interleukin-8, MCP-1, interferon-gamma, dominant-negative mutant, liver inflammation
- MeSH terms
- Animals, Cell Line, Cells, Cultured, Enzyme Activation, Enzyme Induction, Cricetinae, Humans, Liver, Proteins, Signal Transduction, Up-Regulation, Interleukin-8, NF-kappa B, Protein Serine-Threonine Kinases, Chemokines, Chemokine CCL2, CD40 Antigens, Mitogen-Activated Protein Kinases, CD40 Ligand, TNF Receptor-Associated Factor 2, JNK Mitogen-Activated Protein Kinases, I-kappa B Kinase
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