Deletion of interleukin-12p40 suppresses autoimmune cholangitis in dominant negative transforming growth factor β receptor type II mice #

Abstract

Our laboratory has reported that mice that express a dominant negative form of transforming growth factor ␤ receptor restricted to T cells (dnTGF␤RII) develop an inflammatory biliary ductular disease with elevated serum levels of interleukin (IL)-12p40 and other proinflammatory cytokines and antimitochondrial autoantibodies (AMAs) closely resembling human primary biliary cirrhosis (PBC). We have used this mouse model to address the potential mechanisms of immunomodulation of liver disease by creating two unique genetic strains: IL-12p40 knockout (KO)-dnTGF␤RII mice and IFN-␥ KO-dnTGF␤RII mice. The two colonies of genetically modified mice-and, for purposes of controls, the dnTGF␤RII mice-were monitored for liver immunopathology, AMAs, and intrahepatic cytokine production. Disease expression in the IFN-␥ KO-dnTGF␤RII mice, including liver immunopathology, were similar to those of dnTGF␤RII mice, whereas the IL-12p40 KOdnTGF␤RII mice had a dramatic reduction in histological autoimmune cholangitis and significant decreases in levels of intrahepatic proinflammatory cytokines, but similar levels of AMAs compared with dnTGF␤RII controls. Conclusion: These data indicate that in this mouse model of PBC, signaling by way of IL-12p40 is an essential requirement for the development of autoimmune cholangitis. The results of these studies will play an important role in identifying pathways and reagents that will selectively inhibit IL-12 signaling for the outlining of future therapeutic strategies for human PBC.

Primary biliary cirrhosis: From bench to bedside

“…IL-12 consists of the two p35 and p40 subunits, while TGFb signaling is essential in the development of the pro-inflammatory Th17 cells [101] . Further data from this model indicate that it is the p40 subunit which is fundamental for development of bile duct damage [102] . The importance of IL-12 signaling and the PBC-like disease of the dnTGFbRII mice is further supported by genetics relating the IL-12 pathway with human PBC as mentioned in the genetics section [45] .…”

Endogenous interleukin-22 protects against inflammatory bowel disease but not autoimmune cholangitis in dominant negative form of transforming growth factor beta receptor type II mice

“…Pathological changes were evaluated using light microscopy [14,15]. The liver histopathology was graded as: 0, no inflammation (or bile duct damage); 1, mild inflammation (or bile duct damage); 2, moderate inflammation (or bile duct damage); and 3, severe inflammation (or bile duct damage) [15,16]. The colon histopathology was graded as: 0, no significant changes; 1, minimal scattered mucosal inflammatory cell infiltrates, with or without minimal epithelial hyperplasia; 2, mild scattered to diffuse inflammatory cell infiltrates, sometimes extending into the submucosa and associated with erosions, with mild to moderate epithelial hyperplasia and mild to moderate mucin depletion from goblet cells; 3, moderate inflammatory cell infiltrates that were sometimes transmural, with moderate to severe epithelial hyperplasia and mucin depletion; and 4, marked inflammatory cell infiltrates that were often transmural and associated with crypt abscesses and occasional ulceration, with marked epithelial hyperplasia, mucin depletion and loss of intestinal glands [16][17][18].…”

“…In addition, dnTGF-bRII mice develop intrahepatic bile duct-targeted autoimmune disease with substantial similarity to human primary biliary cholangitis (PBC), which is an organ-specific autoimmune disease characterized by destruction of intrahepatic small bile duct epithelial cells [14]. Deletion of IL-12p40 in dnTGF-bRII mice, which results in deficiency of both IL-12 and IL-23, leads to marked diminution of inflammation in both the liver and the colon, indicating that a highly dysregulated Th1/Th17 cell response leads to the development of autoimmune disease [15]. Deletion of IL-23p19 in dnTGF-bRII mice resulted in a marked reduction of the Th17 cell population followed by prevention of colitis, but not cholangitis, suggesting a dominant role of IL-23/Th17 signalling in the pathogenesis of IBD [16].…”

IL-12 Family Cytokines in Inflammation and Bone Erosion of Rheumatoid Arthritis

“…IFN production from Th1 responses is rather suppressing the joint inflammation which was seen in IL-27 suppressing joint inflammation (see section 3.2). Comprehensive studies by using autoimmune disease mouse models with gene knockout mice have demonstrated the complexity of IL-12p40, p35 and its receptors 1 and 2 (Airoldi et al, 2005;Gran et al, 2002;Kikawada, Lenda and Kelley, 2003;Yoshida et al, 2009). IL-12p40 and IL-12 receptor1 gene knockout mice showed resistance to joint inflammation in CIA mice while IL-12p35 and IL-12RII gene knockout mice are significantly more susceptible to joint inflammation induced by collagen type II (Hoeve et al, 2006;Murphy et al, 2003).…”