Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0019158 (
hepatitis
)
30,205
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Fibrosis remains a serious health concern in patients with chronic liver disease. We recently reported that chemically induced chronic murine liver injury triggers increased expression of junctional adhesion molecules (JAMs) JAM-B and
JAM-C
by endothelial cells and de novo synthesis of
JAM-C
by hepatic stellate cells (HSCs). Here, we demonstrate that biopsies of patients suffering from primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) or autoimmune
hepatitis
(AIH) display elevated levels of
JAM-C
on portal fibroblasts (PFs), HSCs, endothelial cells and cholangiocytes, whereas smooth muscle cells expressed
JAM-C
constitutively. Therefore, localization and function of JAM-B and
JAM-C
were investigated in three mouse models of autoimmune-driven liver inflammation. A PBC-like disease was induced by immunization with 2-octynoic acid-BSA conjugate, which resulted in the upregulation of both JAMs in fibrotic portal triads. Analysis of a murine model of PSC revealed a role of
JAM-C
in PF cell-cell adhesion and contractility. In mice suffering from AIH, endothelial cells increased JAM-B level and HSCs and capsular fibroblasts became
JAM-C
-positive. Most importantly, AIH-mediated liver fibrosis was reduced in JAM-B
-/-
mice or when
JAM-C
was blocked by soluble recombinant
JAM-C
. Interestingly, loss of JAM-B/
JAM-C
function had no effect on leukocyte infiltration, suggesting that the well-documented function of JAMs in leukocyte recruitment to inflamed tissue was not effective in the tested chronic models. This might be different in patients and may even be complicated by the fact that human leukocytes express
JAM-C
. Our findings delineate
JAM-C
as a mediator of myofibroblast-operated contraction of the liver capsule, intrahepatic vasoconstriction and bile duct stricture. Due to its potential to interact heterophilically with endothelial JAM-B,
JAM-C
supports also HSC/PF mural cell function. Together, these properties allow JAM-B and
JAM-C
to actively participate in vascular remodeling associated with liver/biliary fibrosis and suggest them as valuable targets for anti-fibrosis therapies.
...
PMID:Junctional adhesion molecules JAM-B and JAM-C promote autoimmune-mediated liver fibrosis in mice. 2975 67
