Inflammation resolved by retinoid X receptor‐mediated inactivation of leukotriene signaling pathways

Abstract

Leukotrienes are implicated in the pathogenesis of diverse, inflammation-driven diseases. Metabolic inactivation of leukotriene signaling is an innate response to resolve inflammation, yet little is known of mechanisms regulating disposition of leukotrienes in peripheral tissues afflicted in common inflammatory diseases. We studied leukotriene hydroxylases (CYP4F gene products) in human skin, a common target of inflammation and adverse drug reactions. Epidermal keratinocytes express at least six CYP4F enzymes; the most highly expressed and highly regulated is CYP4F3A-the main neutrophil leukotriene hydroxylase. Differentiation-specific factors and retinoids are positive CYP4F regulators in vitro, effecting increased leukotriene B4 hydroxylation (inactivation). CYP4F expression is up-regulated in situ in hyperproliferative dermatoses-an innate mechanism to repair and restore epidermal barrier competency-and after retinoid therapy. Enhanced CYP4F-mediated inactivation of leukotriene signaling is a previously unrecognized antiinflammatory property of therapeutic retinoids mediated by preferential interactions between retinoid X receptors and CYP4F promoter elements in epidermal cells.

Gene Regulation ofCYP4F11in Human Keratinocyte HaCaT Cells

“…Abundance of human 18S RNA was used as the internal control. Primers and fluorescent probe sequences for CYP4F11 and 18S RNA were reported (Kalsotra et al, 2008).…”

“…We have previously reported that retinoid treatment of differentiated human primary keratinocytes induced the expression of CYP4F11 and other CYP4F subfamily members, and this induction response seems to be mediated by RAR/RXR heterodimers (Kalsotra et al, 2008). These differences in response to retinoid treatments are likely attributable to FIG.…”

“…Zhang and colleagues showed that retinoic acids and peroxisome proliferators can regulate CYP4F2 gene activities in HepG2 cells, and that retinoid X receptor (RXR) ␣ heterodimers stimulated and retinoic acid receptor (RAR) ␣ repressed CYP4F2 expression Hsu et al, 2007) showed that statins induced CYP4F2 in primary human hepatocytes and HepG2 cells. We recently showed that retinoic acids induced the expression of CYP4F2, CYP4F3A, CYP4F3B, and CYP4F11 in primary human epidermal keratinocytes, and that RXR (but not RAR) nuclear receptors mediate retinoic acid-induced up-regulation of CYP4F2 and CYP4F3A (Kalsotra et al, 2008). In a preliminary study (data not shown) using a transformed immortal human keratinocyte cell line (HaCaT), a different story unfolded.…”

Longitudinal muscle gene expression patterns associated with differential intramuscular fat in cattle

“…CYP4F2 is also involved in long chain and very long chain fatty acid metabolism whereupon the hydroxylated fatty acids are converted to dicarboxylic acids, which are preferentially metabolised in the peroxisome to shorter chain fatty acids that in turn can be processed in the mitochondrion (Hardwick, 2008). CYP4F2 has high affinity for arachidonic acid (Hardwick, 2008), a compound previously explored in the marbling literature, and is also responsive to RA stimulation (Kalsotra et al, 2008). Given the strong relationship between inflammation and adiposity, the observation that an inhibitor of inflammation is relatively downregulated in the high fat, pro-inflammatory Wagyu is noteworthy.…”

Role of Cytochrome P450s in Inflammation

“…The specific expression of CYP4F3A in neutrophils, and its high activity for LTB 4 , suggests that this is a specialized function of the enzyme. CYP-dependent ω-hydroxylation and inactivation of LTB 4 is induced by retinoids in skin cells and might contribute to the beneficial effects of retinoids in the treatment of inflammatory skin diseases (Du, Yin, Morrow, Strobel, & Keeney, 2009;Kalsotra et al, 2008). CYP4F enzymes are also expressed in neurons and glia, and LTB 4 hydroxylase activity limits neuroinflammation in mouse models (Sehgal et al, 2011).…”