Integrin Modulating Factor 1 (IMF-1): A Lipid That Modulated Leukocyte Integrins

Polymorphonuclear leukocytes (PMN) express a receptor of the integrin family termed complement receptor type 3 (CR3, also known as ocMp2, Mac-1, Mol, or CDllb/CD18) that functions in several cell-cell and cell-substratum adhesion events. The capacity of CR3 to mediate adhesion may be rapidly and reversibly enhanced without changes in the number of receptors expressed on the cell surface. This thesis describes an acidic, amphiphilic lipid, termed integrin modulating factor (IMF-1), that may serve to control CR3 avidity. Addition of IMF-1 to cells or to purified CR3 causes enhanced binding of ligand. IMF-1 cannot be extracted from resting PMN but can be extracted from cells within one minute of stimulation with a variety of agonists (PMA, TNF, formylated peptides, platelet activating factor). The amount of IMF-1 extracted declines to low levels within an hour of continued stimulation. The time course of IMF-1 extraction corresponds precisely with the transient increase in the adhesive activity of CR3 observed in PMN stimulated with these agonists. IMF-1 can also increase the binding activity of another leukocyte integrin, LFA-1 (αLβ2, CD1WCD18). However, IMF-1 does not affect the function of representative β1 and β3 integrins. IMF-1 has a molecular weight of 340 + 16 daltons by size exclusion chromatography and appears to be distinct from the known lipid products of PMN. The data suggest that PMN control their adhesivity through a novel lipid that may act as an allosteric activator of leukocyte integrins

Adamantyl Ethanone Pyridyl Derivatives: Potent and Selective Inhibitors of Human 11β-Hydroxysteroid Dehydrogenase Type 1

Elevated levels of active glucocorticoids have been implicated in the development of several phenotypes of metabolic syndrome, such as type 2 diabetes and obesity. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyses the intracellular conversion of inactive cortisone to cortisol. Selective 11β-HSD1 inhibitors have shown beneficial effects in various conditions, including diabetes, dyslipidemia and obesity. A series of adamantyl ethanone pyridyl derivatives has been identified, providing potent and selective inhibitors of human 11β-HSD1. Lead compounds display low nanomolar inhibition against human and mouse 11β-HSD1 and are selective for this isoform, with no activity against 11β-HSD2 and 17β-HSD1. Structure–activity relationship studies reveal that an unsubstituted pyridine tethered to an adamantyl ethanone motif through an ether or sulfoxide linker provides a suitable pharmacophore for activity. The most potent inhibitors have IC50 values around 34–48 nm against human 11β-HSD1, display reasonable metabolic stability in human liver microsomes, and weak inhibition of key human CYP450 enzymes

11 beta-Hydroxysteroid dehydrogenase type 1 contributes to the regulation of 7-oxysterol levels in the arterial wall through the inter-conversion of 7-ketocholesterol and 7 beta-hydroxycholesterol

AbstractThe atherogenic 7-oxysterols, 7-ketocholesterol (7-KC) and 7β-hydroxycholesterol (7βOHC), can directly impair arterial function. Inter-conversion of 7-KC and 7βOHC has recently been shown as a novel role for the glucocorticoid-metabolizing enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Since this enzyme is expressed in vascular smooth muscle cells, we addressed the hypothesis that inter-conversion of 7-KC and 7βOHC by 11β-HSD1 may contribute to regulation of arterial function.Incubation (4–24 h) of aortic rings with either 7-KC (25 μM) or 7βOHC (20 μM) had no effect on endothelium-dependent (acetylcholine) or -independent (sodium nitroprusside) relaxation. In contrast, exposure to 7-KC (but not to 7βOHC) attenuated noradrenaline-induced contraction (Emax) after 4 h (0.78 ± 0.28 vs 0.40 ± 0.08 mN/mm; p < 0.05) and 24 h (2.28 ± 0.34 vs 1.56 ± 0.48 mN/mm; p < 0.05). Both 7-oxysterols were detected by GCMS in the aortic wall of chow-fed C57Bl6/J mice, with concentrations of 7-KC (1.41 ± 0.81 ng/mg) higher (p = 0.05) than 7βOHC (0.16 ± 0.06 ng/mg). In isolated mouse aortic rings 11β-HSD1 was shown to act as an oxo-reductase, inter-converting 7-KC and 7βOHC. This activity was lost in aorta from 11β-HSD1−/− mice, which had low oxysterol levels. Renal homogenates from 11β-HSD1−/− mice were used to confirm that the type 2 isozyme of 11β-HSD does not inter-convert 7-KC and 7βOHC.These results demonstrate that 7-KC has greater effects than 7βOHC on vascular function, and that 11β-HSD1 can inter-convert 7-KC and 7βOHC in the arterial wall, contributing to the regulation of 7-oxysterol levels and potentially influencing vascular function. This mechanism may be important in the cardioprotective effects of 11β-HSD1 inhibitors

Discovery of Adamantyl Heterocyclic Ketones as Potent 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) plays a key role in converting intracellular cortisone to physiologically active cortisol, which is implicated in the development of several phenotypes of metabolic syndrome. Inhibition of 11β-HSD1 activity with selective inhibitors has beneficial effects on various conditions, including diabetes, dyslipidemia and obesity, and therefore constitutes a promising strategy to discover novel therapies for metabolic and cardiovascular diseases. A series of novel adamantyl heterocyclic ketones provides potent and selective inhibitors of human 11β-HSD1. Lead compounds display low nanomolar inhibition against human and mouse 11β-HSD1 and are selective with no activity against 11β-HSD2 and 17β-HSD1. Selected potent 11β-HSD1 inhibitors show moderate metabolic stability upon incubation with human liver microsomes and weak inhibition of human CYP450 enzymes

11β-Hydroxysteroid Dehydrogenase-1 Is a Novel Regulator of Skin Homeostasis and a Candidate Target for Promoting Tissue Repair

11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) catalyzes the interconversion of cortisone and cortisol within the endoplasmic reticulum. 11β-HSD1 is expressed widely, most notably in the liver, adipose tissue, and central nervous system. It has been studied intensely over the last 10 years because its activity is reported to be increased in visceral adipose tissue of obese people. Epidermal keratinocytes and dermal fibroblasts also express 11β-HSD1. However, the function of the enzymatic activity 11β-HSD1 in skin is not known. We found that 11β-HSD1 was expressed in human and murine epidermis, and this expression increased as keratinocytes differentiate. The expression of 11β-HSD1 by normal human epidermal keratinocytes (NHEKs) was increased by starvation or calcium-induced differentiation in vitro. A selective inhibitor of 11β-HSD1 promoted proliferation of NHEKs and normal human dermal fibroblasts, but did not alter the differentiation of NHEKs. Topical application of selective 11β-HSD1 inhibitor to the dorsal skin of hairless mice caused proliferation of keratinocytes. Taken together, these data suggest that 11β-HSD1 is involved in tissue remodeling of the skin. This hypothesis was further supported by the observation that topical application of the selective 11β-HSD1 inhibitor enhanced cutaneous wound healing in C57BL/6 mice and ob/ob mice. Collectively, we conclude that 11β-HSD1 is negatively regulating the proliferation of keratinocytes and fibroblasts, and cutaneous wound healing. Hence, 11β-HSD1 might maintain skin homeostasis by regulating the proliferation of keratinocytes and dermal fibroblasts. Thus 11β-HSD1 is a novel candidate target for the design of skin disease treatments