Activation of pregnane X receptor inhibits experimental dermal fibrosis

Objective: To assess the antifibrotic effects of pregnane X
receptors (PXRs) in experimental dermal fibrosis. Methods: The
antifibrotic effects of PXR activation by 5-pregnen-3
beta-ol-20-one-16 alpha-carbonitrile (PCN) were studied in the
bleomycin model for prevention of dermal fibrosis and the modified
bleomycin model for the treatment of established bleomycin-induced
dermal fibrosis. Activation of canonical transforming growth factor
(TGF)beta signalling was analysed by immunofluorescence staining
for phosphorylated smads. The antifibrotic effects of PXR
activation were further studied in murine fibroblasts and murine T
cells under Th2 conditions. In the T cell experiments, synthesis of
the profibrotic cytokines, interleukin (IL)-4 and IL-13, was
assessed by quantitative PCR, and IL-13 levels in the murine skin
were determined by multiplex bead array technology. Results:
Activation of PXR effectively inhibited the development of
bleomycin-induced dermal fibrosis and induced the regression of
established dermal fibrosis as assessed by skin thickening,
hydroxyproline content and myofibroblasts. Reduced levels of
phosphorylated smad2 and smad3 suggested that the antifibrotic
effects of PXRs were mediated by inhibition of canonical TGF beta
signalling. While PXR activation appeared to have no direct effects
on fibroblasts, it potently inhibited the release of the
profibrotic cytokine, IL-13, from Th2 cells. Consistent with these
findings, IL-13 levels were reduced in bleomycin-challenged murine
skin upon PXR activation. Conclusions: Our findings demonstrate a
novel antifibrotic role for PXRs in inflammatory dermal fibrosis.
The antifibrotic effects of PXRs appear to be indirect: PXR
activation reduces the release of the Th2 cytokine, IL-13, from T
cells resulting in decreased canonical TGF beta signalling.