Biomedical subjects

John S Savill

Publications and source records attributed to John S Savill.

6 recordsLinked to original sources

PubMed2006

Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis.

Apoptosis is essential for clearance of potentially injurious inflammatory cells and subsequent efficient resolution of inflammation. Here we report that human neutrophils contain functionally active cyclin-dependent kinases (CDKs), and that structurally diverse CDK inhibitors induce caspase-dependent apoptosis and override powerful anti-apoptosis signals from survival factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF). We show that the CDK inhibitor R-roscovitine (Seliciclib or CYC202) markedly enhances resolution of established neutrophil-dependent inflammation in carrageenan-elicited acute pleurisy, bleomycin-induced lung injury, and passively induced arthritis in mice. In the pleurisy model, the caspase inhibitor zVAD-fmk prevents R-roscovitine-enhanced resolution of inflammation, indicating that this CDK inhibitor augments inflammatory cell apoptosis. We also provide evidence that R-roscovitine promotes apoptosis by reducing concentrations of the anti-apoptotic protein Mcl-1. Thus, CDK inhibitors enhance the resolution of established inflammation by promoting apoptosis of inflammatory cells, thereby demonstrating a hitherto unrecognized potential for the treatment of inflammatory disorders.

Amino Acid Chloromethyl Ketones↗

PubMed2006

Local amplification of glucocorticoids by 11 beta-hydroxysteroid dehydrogenase type 1 promotes macrophage phagocytosis of apoptotic leukocytes.

Glucocorticoids promote macrophage phagocytosis of leukocytes undergoing apoptosis. Prereceptor metabolism of glucocorticoids by 11beta-hydroxysteroid dehydrogenases (11beta-HSDs) modulates cellular steroid action. 11beta-HSD type 1 amplifies intracellular levels of active glucocorticoids in mice by reactivating corticosterone from inert 11-dehydrocorticosterone in cells expressing the enzyme. In this study we describe the rapid (within 3 h) induction of 11beta-HSD activity in cells elicited in the peritoneum by a single thioglycolate injection in mice. Levels remained high in peritoneal cells until resolution. In vitro experiments on mouse macrophages demonstrated that treatment with inert 11-dehydrocorticosterone for 24 h increased phagocytosis of apoptotic neutrophils to the same extent as corticosterone. This effect was dependent upon 11beta-HSD1, as 11beta-HSD1 mRNA, but not 11beta-HSD2 mRNA, was expressed in these cells; 11-dehydrocorticosterone was ineffective in promoting phagocytosis by Hsd11b1(-/-) macrophages, and carbenoxolone, an 11beta-HSD inhibitor, prevented the increase in phagocytosis elicited in wild-type macrophages by 11-dehydrocorticosterone. Importantly, as experimental peritonitis progressed, clearance of apoptotic neutrophils was delayed in Hsd11b1(-/-) mice. These data point to an early role for 11beta-HSD1 in promoting the rapid clearance of apoptotic cells during the resolution of inflammation and indicate a novel target for therapy.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗

PubMed2006

11Beta-hydroxysteroid dehydrogenase type 1--a role in inflammation?

Glucocorticoids are widely used for their potent anti-inflammatory effects. Endogenous glucocorticoids are immunomodulatory and shape both adaptive and innate immune responses. Over the past decade, it has become apparent that an important level of control over endogenous glucocorticoid action is exerted by the 11beta-hydroxysteroid dehydrogenase enzymes. The type 1 enzyme, 11beta-HSD1, reduces inert glucocorticoids into active forms, thereby increasing intracellular ligand availability to receptors. Although 11beta-HSD1 activity has been shown to play an important role in the metabolic actions of glucocorticoids, its role in the immune response has, until recently, remained unclear. Here we review recent evidence pertaining to the role of 11beta-HSD1 in the inflammatory response.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗

PubMed2006

Local amplification of glucocorticoids by 11beta-hydroxysteroid dehydrogenase type 1 and its role in the inflammatory response.

Glucocorticoids are widely used to treat chronic inflammatory conditions including rheumatoid arthritis. They promote mechanisms important for normal resolution of inflammation, notably macrophage phagocytosis of leukocytes undergoing apoptosis. Prereceptor metabolism of glucocorticoids by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) amplifies intracellular levels of glucocorticoids by oxoreduction of intrinsically inert cortisone (in humans, 11-dehydrocorticosterone in mice) into active cortisol (corticosterone in mice) within cells expressing the enzyme. Recently, we have shown in a mouse model of acute inflammation, high expression of 11beta-HSD oxoreductase but not dehydrogenase activity in cells elicited rapidly in the peritoneum by a single thioglycollate injection. 11beta-HSD oxoreductase activity remained high in peritoneal cells until the inflammation resolved. In vitro, the 11beta-HSD1 substrate, 11-dehydrocorticosterone, increased macrophage phagocytosis of apoptotic neutrophils to the same extent as corticosterone. This effect was dependent upon 11beta-HSD1: these cells solely expressed the type 1 11beta-HSD isozyme (not 11beta-HSD2), and carbenoxolone, an 11beta-HSD inhibitor, prevented the increase in phagocytosis elicited by 11-dehydrocorticosterone. Macrophages from 11beta-HSD1-deficient mice failed to respond to 11-dehydrocorticosterone. In vivo, 11beta-HSD1-deficient mice showed a delay in acquisition of macrophage phagocytic competence and had an increased number of free apoptotic neutrophils during sterile peritonitis. Importantly, in preliminary experiments, 11beta-HSD1-deficient mice exhibited delayed resolution of inflammation in experimental arthritis. These findings suggest 11beta-HSD1 may be a component of mechanisms engaged early during the inflammatory response that promote its subsequent resolution.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗

PubMed2005

Apoptosis in glomerulonephritis.

PURPOSE OF REVIEW: Although glomerular cell apoptosis may be detrimental in acute and chronic inflammation, it is also a key component of the reparative glomerular remodelling that can follow injury. All glomerular cells are vulnerable to apoptosis although there are often differences in the nature of the initiating stimulus and the factors that are protective. The purpose of this review is to outline how modulation of this process may inhibit glomerular injury and promote tissue repair. RECENT FINDINGS: In-vitro studies are providing more information on the factors that regulate apoptosis in individual glomerular cell types. It has now become apparent that growth factors such as vascular endothelial growth factor may have protective actions on several cell types and this may facilitate future treatments that promote the survival of multiple cell types within injured glomeruli. Work in this field has also emphasized that many current treatment strategies may exert a beneficial impact upon renal cell death. SUMMARY: Although the advent of various antiapoptotic agents such as caspase inhibitors and recombinant growth factors does provide future opportunities to modulate apoptosis for therapeutic gain in patients with glomerulonephritis, there is still some way to go before such reagents are used to treat human disease. However, there is scope for optimism that such treatments will reach the clinic in due course.

Animals↗

PubMed2004

Apoptosis in glomerulonephritis.

Apoptosis is of fundamental importance and plays a key role in determining the outcome of glomerulonephritis. Under ideal circumstances,apoptosis deletes infiltrating leukocytes and excess numbers of resident cells that are surplus to requirements, thereby facilitating tissue remodeling and the restoration of normal tissue architecture. Apoptosis also has a darker side, however, and may be responsible for the deletion of critically important resident glomerular cells, resulting in hypocellular scarring and loss of renal function. Recent data indicate that glomerular cell apoptosis may be manipulated to improve outcome in experimental models of renal inflammation. It is hoped that further research will provide novel therapeutic strategies for patients with inflammatory glomerulonephritis.

Apoptosis↗