Hepatic fibrosis is characterized by excess type I collagen deposition and 
exacerbated inflammatory response. Naltrexone, an opioid receptor antagonist 
used for treating alcohol abuse, attenuates hepatocellular injury in fibrotic 
animal models, which can be accompanied by deleterious side effects. 
Additionally, opioid neurotransmission is upregulated in patients with 
inflammatory liver disease. Several derivatives of Naltrexone, Nalmefene (Nal) 
and JKB-119, exert immunomodulatory activity; however, unlike Nal, JKB-119 does 
not show significant opioid receptor antagonism. To delineate the potential 
hepatoprotective effects of these compounds, we investigated if JKB-119 and Nal 
could modulate activation of hepatic stellate cells (HSCs), primary effector 
cells that secrete type I collagen and inflammatory mediators during liver 
injury. Our results demonstrated that Nal or JKB-119 treatment decreased smooth 
muscle α-actin, a marker of HSC activation, mRNA and protein expression. Despite 
decreased collagen mRNA expression, both compounds increased intracellular 
collagen protein expression; however, inhibition of collagen secretion was 
observed. To address a possible mechanism for suppressed collagen secretion or 
retention of intracellular collagen, endoplasmic (ER) protein expression and 
matrix metalloproteinase (MMP) activity were examined. While no change in ER 
protein expression (Grp78, PDI, Hsp47) was observed, MMP13 mRNA expression was 
dramatically increased. In an acute LPS inflammatory injury animal model, 
JKB-119 treatment decreased liver injury (ALT), plasma TNFα and PMN liver 
infiltration. Overall, these results suggest that JKB-119 can directly inhibit 
HSC activation attributed to anti-inflammatory activity and may, therefore, 
attenuate inflammation associated with HSC activation and liver disease.