Biomedical subjects

Duncan S Cole

Publications and source records attributed to Duncan S Cole.

4 recordsLinked to original sources

PubMed2006

p53 regulates cellular resistance to complement lysis through enhanced expression of CD59.

It has been recently hypothesized that the CD59 gene has two putative p53-responsive elements that may be involved in defense of host cells from damage by the complement system in inflammation. Here we have examined the roles of these putative p53-binding sequences within the CD59 gene in regulation of CD59 expression. We have shown that both of these potential responsive elements bind p53 in vitro. Knocking down expression of p53 using small interfering RNA led to a 6-fold decrease in CD59 protein expression in HeLa cells. We have previously observed a decrease of CD59 in camptothecin-induced apoptotic IMR32 cells, whereas expression was increased in the surviving fraction compared with untreated cells. Here, we have shown that these changes are associated with altered expression levels and acetylation status of p53. We have also shown that acetylation status of p53 regulates CD59 expression on cells exposed to inflammatory cytokines to model inflammation. Our data suggest that p53 and in vivo positive/negative regulators of p53 could be used to modulate susceptibility of tumor cells to complement lysis in chemotherapy.

Acetylation↗

PubMed2006

Complement regulator loss on apoptotic neuronal cells causes increased complement activation and promotes both phagocytosis and cell lysis.

In neuroinflammatory disease complement (C) activation and neuronal apoptosis occur in areas of active pathology. C has a role in clearing apoptotic debris, but is also known to cause necrotic cell death by insertion of the membrane attack complex (MAC). It is therefore unclear whether C is protective or injurious in this context. Here we examine C regulator expression and susceptibility to C activation, lysis and phagocytosis in human neuronal cells undergoing apoptosis in order to model the in vivo situation. We demonstrate that apoptotic neuronal lines lose the C regulators CD46 and CD59. Regulator loss occurred only on cells positive for apoptotic markers, and was caspase dependent. Both CD46 and CD59 were shed from cells, CD46 as a soluble form following MMP cleavage, and CD59 on apoptotic blebs and as a soluble form. Apoptotic cells activated C and were opsonised more readily than control cells; as a consequence they were more readily phagocytosed by macrophages than non-apoptotic cells. Susceptibility to C-mediated lysis was complicated in that early cells were more sensitive while late apoptotic cells were more resistant to killing. MMP inhibition protected against the increased lysis seen in early apoptotic cells, but had no effect on susceptibility of non-apoptotic cells to C-mediated lysis. Our studies suggest that C activation on apoptotic neuronal cells is delicately balanced between enhancing their safe disposal through phagocytosis, and triggering necrosis by C-mediated lysis. The data suggest that therapeutic MMP inhibition, by restricting loss of CD46, may limit neuronal damage in neurological disease.

Apoptosis↗

PubMed2005

Novel C5a regulators in inflammatory disease.

Complement is part of the innate immune system, acting to protect the host from microorganisms such as bacteria, and other foreign and abnormal cells. Although primarily protective, complement activation can also cause damage to the host. In a number of inflammatory diseases, including rheumatoid arthritis and dermatitis, there is excessive and inappropriate complement activation. Many of the toxic effects seen in these conditions are attributable to the excessive production of the anaphylatoxin C5a, which may contribute to both the initiation and progression of the disease. Therefore, the regulation of C5a production and modulation of its function are good pharmacological targets in these disorders. As yet, there are no effective agents for the therapeutic regulation of C5a in routine clinical practice. This review describes the role of C5a in inflammatory disease, animal models used to study C5a-related effects, and current strategies aimed at regulating C5a. There is also a discussion of the strengths and weaknesses of these approaches, and an outline of the likely progress of this class of drugs in the future.

Animals↗

PubMed2003

Beyond lysis: how complement influences cell fate.

Complement is a central component of the innate immune system involved in protection against pathogens. For many years, complement has been known to cause death of targets, either indirectly by attracting and activating phagocytes or directly by formation of a membrane pore, the membrane attack complex. More recently, it has been recognized that complement may cause other 'non-classical' effects that may not directly be aimed at killing of pathogens. Products of complement activation collaborate with the adaptive immune system to enhance responses to antigens. The membrane attack complex of complement, apart from lysing cells, can also trigger diverse events in target cells that include cell activation, proliferation, resistance to subsequent complement attack and either resistance to, or induction of, apoptosis. Various complement products play important roles in signalling for clearance by phagocytes of apoptotic self cells. Here we review some of these non-classical activities of complement and stress the roles that they may play in maintaining the integrity of the organism.

Apoptosis↗