Proteins of the complement system are known to interact with many charged substances.We recently characterized binding of C1q and factor H to immobilized and liposomal anionic phospholipids.Factor H inhibited C1q bind...Proteins of the complement system are known to interact with many charged substances.We recently characterized binding of C1q and factor H to immobilized and liposomal anionic phospholipids.Factor H inhibited C1q binding to anionic phospholipids,suggesting a role for factor H in regulating activation of the complement classical pathway by anionic phospholipids.To extend this finding,we examined interactions of C1q and factor H with lipid A,a well-characterized activator of the classical pathway.We report that C1q and factor H both bind to immobilized lipid A,lipid A liposomes and intact Escherichia coli TG1.Factor H competes with C1q for binding to these targets.Furthermore,increasing the factor H:C1q molar ratio in serum diminished C4b fixation,indicating that factor H diminishes classical pathway activation.The recombinant forms of the Cterminal,globular heads of C1q A,B and C chains bound to lipid A and E.coli in a manner qualitatively similar to native C1q,confirming that C1q interacts with these targets via its globular head region.These observations reinforce our proposal that factor H has an additional complement regulatory role of down-regulating classical pathway activation in response to certain targets.This is distinct from its role as an alternative pathway downregulator.We suggest that under physiological conditions,factor H may serve as a downregulator of bacterially-driven inflammatory responses,thereby finetuning and balancing the inflammatory response in infections with Gram-negative bacteria.展开更多
文摘Proteins of the complement system are known to interact with many charged substances.We recently characterized binding of C1q and factor H to immobilized and liposomal anionic phospholipids.Factor H inhibited C1q binding to anionic phospholipids,suggesting a role for factor H in regulating activation of the complement classical pathway by anionic phospholipids.To extend this finding,we examined interactions of C1q and factor H with lipid A,a well-characterized activator of the classical pathway.We report that C1q and factor H both bind to immobilized lipid A,lipid A liposomes and intact Escherichia coli TG1.Factor H competes with C1q for binding to these targets.Furthermore,increasing the factor H:C1q molar ratio in serum diminished C4b fixation,indicating that factor H diminishes classical pathway activation.The recombinant forms of the Cterminal,globular heads of C1q A,B and C chains bound to lipid A and E.coli in a manner qualitatively similar to native C1q,confirming that C1q interacts with these targets via its globular head region.These observations reinforce our proposal that factor H has an additional complement regulatory role of down-regulating classical pathway activation in response to certain targets.This is distinct from its role as an alternative pathway downregulator.We suggest that under physiological conditions,factor H may serve as a downregulator of bacterially-driven inflammatory responses,thereby finetuning and balancing the inflammatory response in infections with Gram-negative bacteria.
