Suppression of hepatocyte CYP1A2 expression by Kupffer cells via AhR pathway: The central role of proinflammatory cytokines

• Published in: International journal of molecular medicine Vol. 18; no. 2; pp. 339 - 346
• Main Authors: Wu, Rongqian, Cui, Xiaoxuan, Dong, Weifeng, Zhou, Mian, Simms, H, Wang, Ping
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01-08-2006
• Subjects: Animals; Aryl Hydrocarbon Receptor Nuclear Translocator - genetics; Aryl Hydrocarbon Receptor Nuclear Translocator - metabolism; Cells, Cultured; Curcumin - metabolism; Cytochrome P-450 CYP1A2 - genetics; Cytochrome P-450 CYP1A2 - metabolism; Cytochromes; Enzyme Inhibitors - metabolism; Hepatocytes - enzymology; Humans; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Isoenzymes - genetics; Isoenzymes - metabolism; Kupffer Cells - cytology; Kupffer Cells - enzymology; Kupffer Cells - physiology; Male; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Aryl Hydrocarbon - genetics; Receptors, Aryl Hydrocarbon - metabolism; Sepsis - metabolism; Signal Transduction - physiology; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism
• DOI: 10.3892/ijmm.18.2.339
• EISSN: 1791-244X
• ISSN: 1107-3756

The hepatic cytochrome P-450 (CYP) enzyme system provides a major aspect
of liver function, yet alterations of CYP in sepsis remain largely unknown. Although
we have recently shown that CYP1A2, one of the major isoforms of CYP in rats,
is downregulated in sepsis, the underlying mechanism and possible therapeutic
approaches warrant further investigation. The aim of this study was to determine
whether Kupffer cells (KCs) play any role in suppressing CYP1A2 in the hepatocytes
(HCs) and if so, how to modulate CYP1A2 expression in sepsis. To study this, primary
KCs and HCs were cultured separately or together with or without transwells. Cells
and supernatant samples were collected after various stimulations. Additionally,
polymicrobial sepsis was induced in rats by cecal ligation and puncture (CLP)
with or without curcumin pretreatment. Liver samples were harvested 20 h post-CLP.
The results show that lipopolysaccharide (LPS) did not suppress CYP1A2 in HC or
HC/KC coculture with transwells. However, LPS downregulated CYP1A2, aryl hydrocarbon
receptor (AhR, a nuclear receptor) and AhR nuclear translocator (Arnt) in coculture
without transwells. Anti-TNF-α and anti-IL-1β antibodies attenuated this downregulation.
Moreover, elevated hepatic levels of TNF-α and IL-1β post-CLP were decreased by
curcumin pre-treatment. This reduction was associated with increased expression
of AhR and CYP1A2. These results indicate that KCs-derived proinflammatory cytokines
may play an important role in downregulating CYP1A2 in sepsis. The reduction of
AhR/Arnt may be the underlying mechanism for such downregulation. Inhibition of
proinflammatory cytokines by curcumin may provide a novel approach to modulate
the hepatic CYP function in sepsis.