title: Interactions of complement proteins C1q and factor H with lipid A and Escherichia coli: further evidence that factor H regulates the classical complement pathway.
abstract: 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 down-regulator. We suggest that under physiological conditions, factor H may serve as a downregulator of bacterially-driven inflammatory responses, thereby fine-tuning and balancing the inflammatory response in infections with Gram-negative bacteria.
authors.affiliation: Medical Research Council Immunochemistry Unit, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX13QU, UK.
authors.forename: Lee Aun
authors.initials: LA
authors.lastname: Tan
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Yang
authors.forename: Uday
authors.initials: U
authors.lastname: Kishore
authors.forename: Robert B
authors.initials: RB
authors.lastname: Sim
mesh_terms: D001667:Binding, Competitive / Q000276:immunology; D003167:Complement Activation / Q000276:immunology*; D015922:Complement C1q / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D015935:Complement C4b / Q000032:analysis; D017242:Complement Factor H / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D003171:Complement Pathway, Classical / Q000276:immunology*; D004926:Escherichia coli / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007457:Iodine Radioisotopes; D007553:Isotope Labeling; D008050:Lipid A / Q000276:immunology / Q000378:metabolism; D008081:Liposomes / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D011994:Recombinant Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D007457:Iodine Radioisotopes; D008050:Lipid A; D008081:Liposomes; D011994:Recombinant Proteins; D015922:Complement C1q; D015935:Complement C4b; D017242:Complement Factor H