Regulation of CYP4A1 and peroxisome proliferator-activated receptor alpha expression by interleukin Iβ, interleukhv 6, and dexamethasone in cultured fetal rat hepatocytes

Abstract

The CYP4A1 isoenzyme induced in rodents by peroxisome proliferators is known to be repressed at a pretranslational level by interferon. Interleukin'lβ (IL-1β) also reduces CYP4A1-related 12-laurate hydroxylase activity in cultured fetal rat hepatocytes after induction by clofibric acid. In this fetal hepatocyte model, IL-lβ and interleukin-6 (IL-6) were tested for their ability to reduce 12-laurate hydroxylase activity, CYP4A1 apoprotein content, and the CYP4A1 mRNA level. IL-1β and IL-6 strongly diminished CYP4A1 activity and apoprotein and mRNA levels in a dose- and time-dependent manner. CYP4A1 expression is thus down-regulated at a pretranslational level by these cytokines. As it has been shown that the peroxisome proliferator-activated receptor alpha (PPARa) mediates the induction of the CYP4A1 gene by a peroxisome proliferator, the capacity of IL-1β or IL-6 to modulate the PPARa mRNA level was tested. It was found that IL-1β and IL-6 both repress the induction of PPARa expression exerted by the combined action of clofibric acid and dexamethasone. However, even at the highest concentration (10 ng/mL) tested for both cytokines, IL-lβ as well as IL-6 failed to abolish the induction of CYP4A1 by dexamethasone. The mechanism of the protective effect of the synthetic glucocorticoid on CYP4A1 repression by interleukins is discussed.