Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0239946 (liver fibrosis)
 8,268 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chemokines are the inflammatory mediators that modulate liver fibrosis, a common feature of chronic inflammatory liver diseases. CX3CL1/fractalkine is a membrane-associated chemokine that requires step processing for chemotactic activity and has been recently implicated in liver disease. Here, we investigated the potential shedding activities involved in the release of the soluble chemotactic peptides from CX3CL1 in the injured liver. We showed an increased expression of the sheddases ADAM10 and ADAM17 in patients with chronic liver diseases that was associated with the severity of liver fibrosis. We demonstrated that hepatic stellate cells (HSC) were an important source of ADAM10 and ADAM17 and that treatment with the inflammatory cytokine inter-feron-gamma induced the expression of CX3CL1 and release of soluble peptides. This release was inhibited by the metalloproteinase inhibitor batimastat; however, ADAM10/ADAM17 inhibitor GW280264X only partially affected shedding activity. By using selective tissue metalloprotease inhibitors and overexpression analyses, we showed that CX3CL1 was mainly processed by matrix metalloproteinase (MMP)-2, a metalloprotease highly expressed by HSC. We further demonstrated that the CX3CL1 soluble peptides released from stimulated HSC induced the activation of the CX3CR1-dependent signalling pathway and promoted chemoattraction of monocytes in vitro. We conclude that ADAM10, ADAM17 and MMP-2 synthesized by activated HSC mediate CX3CL1 shedding and release of chemotactic peptides, thereby facilitating recruitment of inflammatory cells and paracrine stimulation of HSC in chronic liver diseases.
 ...
PMID:CX3CL1/fractalkine shedding by human hepatic stellate cells: contribution to chronic inflammation in the liver. 1943 9

Sustained inflammation upon chronic liver injury induces the development of liver fibrosis in mice and men. Experimental models of liver fibrosis highlight the importance of hepatic macrophages, so-called Kupffer cells, for perpetuating inflammation by releasing proinflammatory cytokines and chemokines as well as activating hepatic stellate cells (HSC). Recent studies in mice demonstrate that these actions are only partially conducted by liver-resident macrophages, classically termed Kupffer cells, but largely depend on recruitment of monocytes into the liver. Monocytes are circulating precursors of tissue macrophages and dendritic cells (DC), which comprise two major subsets in blood, characterized by the differential expression of chemokine receptors, adhesion molecules and distinct markers, such as Ly6C/Gr1 in mice or CD14 and CD16 in humans. Upon organ injury, chemokine receptor CCR2 and its ligand MCP-1 (CCL2) as well as CCR8 and CCL1 promote monocyte subset accumulation in the liver, namely of the inflammatory Ly6C(+) (Gr1(+)) monocyte subset as precursors of tissue macrophages. The infiltration of proinflammatory monocytes into injured murine liver can be specifically blocked by novel anti-MCP-1 directed agents. In contrast, chemokine receptor CX3CR1 and its ligand fractalkine (CX3CL1) are important negative regulators of monocyte infiltration in hepatic inflammation by controlling their survival and differentiation into functionally diverse macrophage subsets. In patients with liver cirrhosis, 'non-classical' CD14(+)CD16(+) monocytes are found activated in blood as well as liver and promote pro-inflammatory along with pro-fibrogenic actions by the release of distinct cytokines and direct interactions with HSC, indicating that the findings from murine models can be translated into pathogenesis of human liver fibrosis. Moreover, experimental animal models indicate that monocytes/macrophages and DCs are not only critical for fibrosis progression, but also for fibrosis regression, because macrophages can also degrade extracellular matrix proteins and exert anti-inflammatory actions. The recently identified cellular and molecular pathways for monocyte subset recruitment, macrophage differentiation and interactions with other hepatic cell types in injured liver may therefore represent interesting novel targets for future therapeutic approaches in liver fibrosis.
...
PMID:Functional role of intrahepatic monocyte subsets for the progression of liver inflammation and liver fibrosis in vivo. 2325 11